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MAPK

SB203580 inhibits epithelial-mesenchymal transition and pulmonary fibrosis in a rat silicosis model

15 | Oct 12 2019

Yan W et al. suggested that p38 MAPK/ZEB-1 (ZEB-2, Twist) pathway was involved at 7days after silica instillation and p38 MAPK was pivotal for EMT in silicosis fibrosis in rats. [Read the Full Post]

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma

10 | Sep 25 2019

Long GV et al. indicated that adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. [Read the Full Post]

Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex

14 | Sep 24 2019

Konermann S et al. demonstrated the potential of Cas9-based activators as a powerful genetic perturbation technology. [Read the Full Post]

Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas

17 | Sep 01 2019

Dombi E et al. suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. [Read the Full Post]

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study

14 | Sep 01 2019

Banerjee A et al. indicated that selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs. [Read the Full Post]

RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models

39 | Aug 29 2019

Yang H et al. indicated their findings offer evidence of the potent antitumor activity of RG7204 against melanomas harboring the mutant BRAF(V600E) gene. [Read the Full Post]

Inhibition of glioblastoma dispersal by the MEK inhibitor PD0325901

21 | Aug 21 2019

Shannon S et al. showed that PD0325901 significantly increases aggregate cohesion, stiffness, and viscosity but only when tumor cells have access to high concentrations of fibronectin. Treatment also results in reorganization of actin from cortical into stress fibers, in both 2D and 3D culture. Moreover, drug treatment localized pFAK at sites of cell-substratum adhesion. Collectively, these changes resulted in increased strength of substrate attachment and decreased motility, a decrease in aggregate dispersal velocity, and in a marked decrease in growth rate of both 2D and 3D cultures. [Read the Full Post]

Human primary liver cancer-derived organoid cultures for disease modeling and drug screening

27 | Aug 04 2019

Broutier L et al. demonstrated the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease. [Read the Full Post]

Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α

29 | Jul 26 2019

Qiu Y et al. indicated that miR-16/14-3-3η is involved in sorafenib resistance in HCC and that these two factors could be potential therapeutic targets and biomarkers for predicting the response to sorafenib treatment. [Read the Full Post]

GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition

25 | Jul 21 2019

Gilmartin AG et al. showed that GSK1120212 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clinical MEK inhibitors. [Read the Full Post]

A high-performance liquid chromatography-tandem mass spectrometry method for the determination of lifrafenib, a novel RAF kinase and EGFR inhibitor, in human plasma and urine and its application in clinical pharmacokinetic study

62 | Jul 01 2019

Yao X et al. showed robust and sensitive, it successfully fulfilled the requirement of clinical pharmacokinetic study of lifirafenib in Chinese patients with locally advanced or metastatic solid tumors. [Read the Full Post]

Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic

30 | Jun 28 2019

Ramurthy S et al. indicated that a structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials. [Read the Full Post]

A DSTYK mutation activates ERK1/2 signaling to promote intraspinal dissemination in a case of solitary fibrous tumor/hemangiopericytoma

45 | Jun 18 2019

Tang G et al. revealed the potential role of DSTYK mutation in the regulation of intraspinal metastasis of SFT/HPC, which might provide new biological insights into this rare disease. [Read the Full Post]

Trametinib Induces Neurofibroma Shrinkage and Enables Surgery

55 | Jun 11 2019

Vaassen P et al. suggested that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1. [Read the Full Post]

Regulation of cisplatin-resistant head and neck squamous cell carcinoma by the SRC/ETS-1 signaling pathway

45 | Jun 06 2019

Yang Z et al. demonstrated that the SRC/ETS-1 pathway plays a crucial role and could be a key therapeutic target in cisplatin-resistant HNSCC treatment. [Read the Full Post]

Differential effects of p38 MAP kinase inhibitors SB203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line

43 | Jun 05 2019

Düzgün ŞA et al. indicated the ERK1/2 phosphorylation level was not modified by low concentrations (1 or 5 µM) of SB202190 and SB203580; while a high concentration (50 µM) of both inhibitors caused significant reductions in the ERK1/2 phosphorylation. In addition, it was determined that both p38 MAPK inhibitors caused significant increases on the Ser15 phosphorylation of mutant p53 in MDA-MB-231 under these experimental conditions; while SB202190 was more potent than SB203580. [Read the Full Post]

Targeting ERK1/2 protein-serine/threonine kinases in human cancers

0 | May 29 2019

Roskoski R Jr indicated that Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors. These agents are effective against cell lines that are resistant to B-Raf and MEK1/2 inhibitor therapy. Although MK-8353 does not directly inhibit MEK1/2, it decreases the phosphorylation of ERK1/2 as well as the phosphorylation of RSK, an ERK1/2 substrate. The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway. [Read the Full Post]

A novel anti-melanoma SRC-family kinase inhibitor.

67 | May 24 2019

Halaban R suggested that the new compound could be used in the clinic as a substitute for, or in combination with MAPK inhibitors. [Read the Full Post]

Targeting ERK1/2 protein-serine/threonine kinases in human cancers

0 | May 23 2019

Roskoski R Jr showed that Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors. These agents are effective against cell lines that are resistant to B-Raf and MEK1/2 inhibitor therapy. Although MK-8353 does not directly inhibit MEK1/2, it decreases the phosphorylation of ERK1/2 as well as the phosphorylation of RSK, an ERK1/2 substrate. The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway. [Read the Full Post]

Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study

50 | May 16 2019

Long GV et al. demonstrated that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting. [Read the Full Post]

Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations

52 | May 15 2019

Greger JG et al. showed that NRAS and/or MEK mutations contribute to BRAF inhibitor resistance in vitro, and the combination of GSK2118436 and GSK1120212 overcomes this resistance. [Read the Full Post]

Simultaneous long-lasting regression of multiple nevi and melanoma metastases after ipilimumab therapy

70 | May 03 2019

Plaquevent M et al. suggested that a major regression of multiple nevi on ipilimumab might be associated with immunotherapy response. [Read the Full Post]

Vemurafenib Treatment of Pleomorphic Xanthoastrocytoma in a Child With Down Syndrome

65 | May 02 2019

Petruzzellis G et al. report the case of an 8-years-old child with DS that presented to our attention for neurological and endocrinological issues. [Read the Full Post]

Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells

58 | May 02 2019

Mito-CP-induced cell death was partially rescued by mortalin overexpression, suggesting that Mito-CP may inactivate a mechanism that requires mortalin function. These findings support the significance of mortalin and mitochondrial activity in a broad spectrum of thyroid cancer. [Read the Full Post]

Targeting ERK1/2 protein-serine/threonine kinases in human cancers

73 | Apr 28 2019

Roskoski R Jr indicated that Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors. These agents are effective against cell lines that are resistant to B-Raf and MEK1/2 inhibitor therapy. Although MK-8353 does not directly inhibit MEK1/2, it decreases the phosphorylation of ERK1/2 as well as the phosphorylation of RSK, an ERK1/2 substrate. The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway. [Read the Full Post]

Quantitative Interrogation of the Human Kinome Perturbed by Two BRAF Inhibitors

76 | Apr 27 2019

We confirmed that vemurafenib could compromise the ATP binding capacity of MAP2K5 in vitro and inhibit its kinase activity in cells. [Read the Full Post]

A possible mechanism for hepatotoxicity induced by BIRB-796, an orally active p38 mitogen-activated protein kinase inhibitor

80 | Apr 25 2019

Iwano S et al. indicated that a reactive intermediate of BIRB-796 was detected by the glutathione-trapping method using mouse and human liver microsomes. The production of this reactive metabolite in the liver may be one of the causes of BIRB-796's hepatotoxicity. [Read the Full Post]

In vitro anti-osteoclastogenic activity of p38 inhibitor doramapimod via inhibiting migration of pre-osteoclasts and NFATc1 activity

86 | Apr 17 2019

Moon SH et al. suggested anti-osteoclastogenic activity of doramapimod via inhibiting migration/fusion of pre-osteoclasts and NFATc1 activity. [Read the Full Post]

Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial

105 | Apr 03 2019

Planchard D et al. found that Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAFV600E-mutant NSCLC. [Read the Full Post]

Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia

85 | Feb 11 2019

Campbell CT et al. demonstrated TER models of the DOT1L inhibitor pinometostat and provided useful tools for investigating clinical resistance. [Read the Full Post]

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

112 | Jan 26 2019

Diamond EL et al. highlighted the importance of comprehensive genomic analysis of these disorders. [Read the Full Post]

MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation

258 | Jan 21 2019

Zhao Y et al. may elucidate a possible mechanism explaining the ineffectiveness of MEK inhibitors in breast cancer treatment and improve our understanding of the role of MEK in cancer. [Read the Full Post]

Down-Regulation of AQP4 Expression via p38 MAPK Signaling in Temozolomide-Induced Glioma Cells Growth Inhibition and Invasion Impairment

196 | Jan 19 2019

Chen Y et al. identified that TMZ might have therapeutic potential for controlling proliferation, invasion of malignant glioma by inhibiting AQP4 expression through activation of p38 signal transduction pathway. [Read the Full Post]

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

140 | Nov 29 2018

Niessner H et al. presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma. [Read the Full Post]

DCLK1 is correlated with MET and ERK5 expression, and associated with prognosis in malignant pleural mesothelioma

135 | Nov 22 2018

Wang H et al. suggested that DCLK1 is regulated by MET/ERK5 signaling in human mesothelioma, and the MET/ERK5/DCLK1 signaling cascade could be further developed into a promising therapeutic target against mesothelioma. [Read the Full Post]

Oncogenic KRas-induced Increase in Fluid-phase Endocytosis is Dependent on N-WASP and is Required for the Formation of Pancreatic Preneoplastic Lesions

168 | Nov 17 2018

Lubeseder-Martellato C et al. defined a new role of FPE as a tumor initiating mechanism. [Read the Full Post]

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

188 | Nov 12 2018

Zhou H et al. provided a potential target for diagnosis and therapeutic treatment of breast cancer. [Read the Full Post]

Pro-survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

0 | Nov 06 2018

Chen Y et al. showed that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of cyclin-dependent kinase inhibitors in CLL in combination with other relevant targeted therapies. [Read the Full Post]

PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib]

519 | Oct 19 2018

Booth L et al. argued that additional clinical studies combining pemetrexed, sorafenib and sildenafil are warranted. [Read the Full Post]

The selective MEK1 inhibitor Selumetinib enhances the antitumor activity of everolimus against renal cell carcinoma in vitro and in vivo

199 | Oct 17 2018

Zou Y et al. provided a sound evidence that combination of everolimus and Selumetinib is a potential dual-targeted strategy for renal cell carcinoma. [Read the Full Post]

Honokiol Induces Apoptosis, G1 Arrest, and Autophagy in KRAS Mutant Lung Cancer Cells

708 | Aug 22 2018

Luo LX et al. indicated these results broaden our understanding of the mechanisms on honokiol effects in lung cancer, and reinforce the possibility of its potential anticancer benefit as a popular Chinese herbal medicine (CHM). [Read the Full Post]

Nesfatin-1 protects dopaminergic neurons against MPP+/MPTP-induced neurotoxicity through the C-Raf-ERK1/2-dependent anti-apoptotic pathway

0 | Jul 02 2018

Shen XL et al. suggested that C-Raf-ERK1/2, which is involved in an anti-apoptotic pathway, is responsible for the neuroprotective effects of nesfatin-1 in the context of MPTP-induced toxicity. These results imply that nesfatin-1 might have therapeutic potential for PD. [Read the Full Post]

miR-7 reverses the resistance to BRAFi in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways

319 | Jul 01 2018

Sun X et al. demonstrated that miR-7 could reverse the resistance to BRAF inhibitors in certain vemurafenib resistant melanoma cell lines. It could advance the field and provide the basis for further studies in BRAF inhibitor resistance in melanoma. [Read the Full Post]

Identification of approved and investigational drugs that inhibit hypoxia-inducible factor-1 signaling

550 | Jun 27 2018

Hsu CW et al. underline the importance of developing a battery of robust assay platforms and confirmation studies that focus on endogenous protein targets so that only relevant and reliable data will be taken into pre-clinical and clinical studies. [Read the Full Post]

Ionizing Radiation Induces Altered Neuronal Differentiation by mGluR1 through PI3K-STAT3 Signaling in C17.2 Mouse Neural Stem-Like Cells

301 | Jun 22 2018

Eom HS et al. suggested that the IR-induced altered neuronal differentiation may play a role in the brain dysfunction caused by IR. [Read the Full Post]

A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

394 | Jun 22 2018

Jeric I et al. indicated the contribution of the cellular/tissue environment in determining the function of a protein, and underscores the importance of understanding the molecular context of a disease to inform therapy design. [Read the Full Post]

Registered report: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

304 | Jun 21 2018

Bhargava A et al. indicated that cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife. [Read the Full Post]

RAD51 inhibition in triple negative breast cancer cells is challenged by compensatory survival signaling and requires rational combination therapy

289 | Jun 13 2018

Wiegmans AP et al. highlight a potential compensatory mechanism via p38 that limits DNA targeted therapy. [Read the Full Post]

Registered report: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF

310 | Jun 11 2018

Bhargava A et al. indicated that Heidorn and colleagues report that paradoxical activation of the RAF-RAS-MEK-ERK pathway by BRAF inhibitors when applied to BRAF(WT) cells is a result of BRAF/CRAF heterodimer formation upon inactivation of BRAF kinase activity, and occurs only in the context of active RAS. [Read the Full Post]

Proliferation of the human urothelium is induced by atypical β1 -adrenoceptors

386 | Jun 05 2018

Winder M et al. showed that the urothelium expresses atypical β1-adrenoceptors that activate intracellular kinases inducing urothelial proliferation. [Read the Full Post]

Signaling effects of sodium hydrosulfide in healthy donor peripheral blood mononuclear cells

396 | Jun 04 2018

Sulen A et al. provided a description of a NaHS-induced signal transduction pathway in human primary immune cells that may have relevance for the role of sulfides in inflammation. [Read the Full Post]

Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events

301 | May 24 2018

Yang P et al. indicated that loss of SMC-Tgfbr1 triggers multiple deleterious pathways, including abnormal TGFBR2, ERK, and AngII/AT1R signals that disrupt aortic wall homeostasis to cause aortic aneurysm formation. [Read the Full Post]

Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells

364 | May 23 2018

Gonçalves-Ribeiro S et al. showed that STAT3 or P38 inhibition provides a promising strategy for overcoming microenvironment-mediated resistance. Conversely, pharmacologic AKT inhibition induces an antagonistic effect that relieves a cMET and STAT3-mediated compensatory feedback that might explain the failure of AKT inhibitors in the clinic so far. [Read the Full Post]

Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines

358 | May 23 2018

Fernández ML et al. showed the greatest anti-proliferative effects. This study serves as a basis for much needed future research on MEKi drug efficacy in LGSC. [Read the Full Post]

DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival

307 | May 22 2018

Wingert S et al. indicated that genotoxic stress-induced GADD45A expression in HSCs prevents their fatal transformation by directing them into differentiation and thereby clearing them from the system. [Read the Full Post]

Connexin 32-mediated cell-cell communication is essential for hepatic differentiation from human embryonic stem cells

505 | Apr 22 2018

Qin J et al. suggested that Cx32 is essential for cell-cell interactions that facilitate driving hESCs through hepatic-lineage maturation. Regulators of both Cx32 and other members of its pathways maybe used as a promising approach on regulating hepatic lineage restriction of pluripotent stem cells and optimizing their functional maturation. [Read the Full Post]

Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth

555 | Mar 31 2018

Dewaele M et al. concluded that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target. [Read the Full Post]

Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response

971 | Feb 27 2018

Luo Y et al. identified Tsc1 as a crucial signaling checkpoint in DCs essential for preserving T-cell homeostasis and response. [Read the Full Post]

Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance

386 | Feb 23 2018

Shaffer SM et al. found that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general program in which expression is displayed in rare subpopulations of cells. [Read the Full Post]

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

558 | Feb 12 2018

He H et al. indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ. [Read the Full Post]

Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

478 | Feb 06 2018

El Bezawy R et al. showed impressive inhibitory effects induced by miR-34a on DMPM cell proliferation, invasion, and growth in immunodeficient mice strongly suggest the potential clinical utility of a miR-34a-replacement therapy for the treatment of such a still incurable disease. On the other hand, we provide the first evidence of a potential cytoprotective/resistance mechanism that may arise towards miRNA-based therapies through the persistent activation of RTK downstream signaling. [Read the Full Post]

Pan-Raf co-operates with PI3K-dependent signalling and critically contributes to myeloma cell survival independently of mutated RAS

393 | Jan 30 2018

Müller E et al. indicated concomitant pan-Raf/PI3K inhibition was also effective in carfilzomib- and lenalidomide-resistant MM models underscoring that this attractive therapeutic anti-MM strategy is suitable for immediate clinical translation. [Read the Full Post]

ERK5 activation is essential for osteoclast differentiation

406 | Jan 29 2018

Amano S et al. showed that activation of the MEK5/ERK5 pathway with M-CSF is required for osteoclast differentiation, which may induce differentiation through the induction of c-Fos. [Read the Full Post]

Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells

437 | Jan 28 2018

Boutin A et al. concluded that TSH regulates expression of different bone markers via distinct signaling pathways. [Read the Full Post]

The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer

0 | Jan 24 2018

Beadnell TC et al. demonstrated that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single-agent inhibition. [Read the Full Post]

Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer

470 | Jan 23 2018

Queralt B et al. showed that synthetic lethal interaction of cetuximab in combination with MEK1/2 inhibition for the NRAS mutant subgroup of mCRC underscores the importance of therapeutic intervention both in the MEK-ERK and EGFR pathways to achieve maximal therapeutic efficacy against NRAS-mutant mCRC tumors. [Read the Full Post]

Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines

435 | Jan 23 2018

Fernández ML et al. showed the greatest anti-proliferative effects. This study serves as a basis for much needed future research on MEKi drug efficacy in LGSC. [Read the Full Post]

Vascular CXCR4 Expression Promotes Vessel Sprouting and Sensitivity to Sorafenib Treatment in Hepatocellular Carcinoma

653 | Dec 22 2017

Xu J et al. revealed that CXCR4 is a novel HCC vascular marker for vessel sprouting and could serve as a potential therapeutic target and a predictive factor for sorafenib treatment in patients with HCC. [Read the Full Post]

Effect of earthworm active protein on fibroblast proliferation and its mechanism

571 | Dec 09 2017

Song S et al. demonstrated that EAP is effective in promoting effects on proliferation and migration activity of NIH3T3 cell, and the proliferation activity of EAP on NIH3T3 cell may be achieved through the PI3K→Rac→PAK→MEK signaling pathway. [Read the Full Post]

Icaritin activates JNK-dependent mPTP necrosis pathway in colorectal cancer cells

0 | Dec 01 2017

Zhou C et al. showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. JNK-dependent mPTP necrosis pathway could be key mechanism responsible for ICT's actions. [Read the Full Post]

An Optimized Chromatographic Strategy for Multiplexing In Parallel Reaction Monitoring Mass Spectrometry: Insights from Quantitation of Activated Kinases

514 | Nov 20 2017

Urisman A et al. obtained from these analyses reveal compensatory activation of TGF-β family receptors as a response to MAPK blockade. The gains achieved using this label-free PRM multiplexing strategy will benefit a wide array of biological applications. [Read the Full Post]

CQ synergistically sensitizes human colorectal cancer cells to SN-38/CPT-11 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk

907 | Nov 18 2017

Chen P et al. showed that CQ could enhance CRC cells response to CPT-11 (a prodrug of SN-38) in xenograft models. Thus the combined treatment might represent an attractive therapeutic strategy for the treatment of CRC. [Read the Full Post]

NMR Characterization of Information Flow and Allosteric Communities in the MAP Kinase p38γ

1386 | Nov 16 2017

Aoto PC et al. demonstrated that the approach detects critical junctions in the network corresponding to biologically significant allosteric sites and pathways. [Read the Full Post]

Icaritin activates JNK-dependent mPTP necrosis pathway in colorectal cancer cells

809 | Nov 11 2017

Zhou C et al. showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. [Read the Full Post]

Hepatocyte growth factor reduces sensitivity to the epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib, in lung adenocarcinoma cells harboring wild-type EGFR

0 | Nov 02 2017

Yang H et al. suggested that HGF reduced the gefitinib sensitivity through MET and downstream PI3K and MAPK pathways. [Read the Full Post]

Enhancement of macrophage inflammatory responses by CCL2 is correlated with increased miR-9 expression and downregulation of the ERK1/2 phosphatase Dusp6

589 | Oct 29 2017

Carson WF 4th et al. indicated that CCL2 supports the classical activation of macrophages, with miR-9 mediated down-regulation of Dusp6 and enhanced ERK-mediated signal transduction possibly mediating this enhanced pro-inflammatory gene expression. [Read the Full Post]

SP600125 enhances the anti-apoptotic capacity and migration of bone marrow mesenchymal stem cells treated with tumor necrosis factor-α

810 | Oct 11 2017

Wei B et al. suggested that SP600125 is of potential use in promoting the regeneration of bone and cartilage in OA and RA. [Read the Full Post]

Effects of bavachin and its regulation of melanin synthesis in A375 cells

0 | Oct 10 2017

Wang JH, et al. found that bavachin inhibited the synthesis of melanin on A375 cells by inhibiting the protein and mRNA expression of TYR, TRP-1, TRP-2, ERK1, ERK2 andJNK2. [Read the Full Post]

Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4

0 | Oct 08 2017

Zeng Q et al. provided critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4. [Read the Full Post]

MEK inhibitor CI-1040 induces apoptosis in acute myeloid leukemia cells in vitro

565 | Oct 07 2017

Wei CR et al. demonstrated that CI-1040 induce apoptosis of U-937 cells and might be a new therapeutic option for the treatment of AML. [Read the Full Post]

Effect of earthworm active protein on fibroblast proliferation and its mechanism

0 | Oct 01 2017

Song S et al. demonstrated that EAP is effective in promoting effects on proliferation and migration activity of NIH3T3 cell, and the proliferation activity of EAP on NIH3T3 cell may be achieved through the PI3K→Rac→PAK→MEK signaling pathway. [Read the Full Post]

Multiplexed Fluorescence Imaging of ERK and Akt Activities and Cell-cycle Progression

0 | Sep 18 2017

Maryu G et al. provided a useful tool for quantifying the dynamics among ERK and Akt activities and the cell cycle in a live cell, and for addressing the mechanisms underlying intrinsic resistance to molecularly targeted drugs. [Read the Full Post]

BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2

0 | Sep 08 2017

Zhang ZX et al. indicated that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis. [Read the Full Post]

TIMP-1 expression induced by IL-32 is mediated through activation of AP-1 signal pathway

0 | Aug 18 2017

Xu H, et al. believed that IL-32 might be involved in the pathogenesis of hepatic fibrosis by inducing TIMP-1 expression. [Read the Full Post]

Phosphorylation of the RNA-binding protein Dazl by MAPKAP kinase 2 regulates spermatogenesis

0 | Aug 18 2017

Williams PA et al. suggested that signaling by the p38-MK2 pathway is a negative regulator of spermatogenesis via phosphorylation of Dazl. [Read the Full Post]

Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein-Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression

0 | Aug 12 2017

Jones RJ et al. concluded LTP may reactivate EBV-positive resting memory B cells thereby enhancing EBV lytic cycle and host immune suppression [Read the Full Post]

TGF-β1 promotes Staphylococcus aureus adhesion to and invasion into bovine mammary fibroblasts via the ERK pathway

1370 | Aug 07 2017

Zhao S et al. indicated that TGF-β1 could promote S. aureus adhesion to and invasion into BMFBs by increasing Collagen I and α-SMA expression and may provide a novel target for controlling bovine mastitis. [Read the Full Post]

Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis

653 | Jul 19 2017

Lu YX et al. suggest that nafamostat mesilate, a relatively non-toxic drug that targets NF-κB and Erk, may, in combination with oxaliplatin, represent a novel therapeutic strategy for CRC treatment. [Read the Full Post]

Analysis of Endogenous Protein Interactions of Polycomb Group of Proteins in Mouse Embryonic Stem Cells

0 | Jul 06 2017

Morey L et al. described several methods to study Polycomb architecture, and identification of novel interactors in both pluripotent and differentiating mouse embryonic stem cells. [Read the Full Post]

Inhibition of acquired-resistance hepatocellular carcinoma cell growth by combining sorafenib with phosphoinositide 3-kinase and rat sarcoma inhibitor

777 | Jul 06 2017

J Surg Res have showed that both inhibitors of PI3K/mTOR and RAS/ERK signaling are potentially effective antihepatocellular carcinoma drugs especially in treating sorafenib-resistant hepatocellular carcinoma. [Read the Full Post]

The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib

829 | Jul 05 2017

Park KS et al. showed that intrinsic resistance to MEK inhibition occurred via high AKT expression by PI3K activation as a bypass pathway. The HSP90 inhibitor AUY922 suppressed PI3K-AKT-mTOR and RAF-MEK-ERK, and rendered cells sensitive to trametinib (GSK1120212). Synergy from the combination of the two drugs was observed in only sub-therapeutic concentrations of either drug. Dual inhibition of the HSP90 and MEK signaling pathways with sub-therapeutic doses may represent a potent therapeutic strategy to treat KRAS-mutant NSCLC with intrinsic resistance to MEK inhibition and to resolve the toxicity observed upon dual inhibition of AKT and MEK at therapeutic doses in clinical trials. [Read the Full Post]

Adiponectin promotes human jaw bone marrow mesenchymal stem cell chemotaxis via CXCL1 and CXCL8

2011 | Jul 02 2017

Pu Y et al. suggested that APN can promote h-JBMMSC chemotaxis by up-regulating CXCL1 and CXCL8. [Read the Full Post]

The mechanically activated p38/MMP-2 signaling pathway promotes bone marrow mesenchymal stem cell migration in rats

826 | Jul 02 2017

Yang Z et al. demonstrated that static strain can promote the migration ability of BMMSCs via p38/MMP-2 signaling. To the best of our knowledge, this study is the first report demonstrating that the p38/MMP-2 axis governs BMMSC migration under static mechanical strain. [Read the Full Post]

Cdk5 is required for the neuroprotective effect of transforming growth factor-β1 against cerebral ischemia-reperfusion

2220 | Jun 21 2017

Zhao W et al. concluded that Cdk5 contributes to the neuroprotective function of TGF- β1 via ERK1/2 signaling. [Read the Full Post]

Hypoxia-induced vasculogenic mimicry formation in human colorectal cancer cells: Involvement of HIF-1a, Claudin-4, and E-cadherin and Vimentin.

802 | Jun 20 2017

Li W et al. revealed a regulatory role for HIF-1α in VM and suggests that targeting either HIF-1α or EMT may be a valuable strategy for the elimination of CRC metastasis. [Read the Full Post]

Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, in KRAS-Mutant NSCLC Is Mediated via Reactivation of the ERK-p90RSK-mTOR Signaling Network

1594 | Jun 20 2017

Chatterjee S et al. offered a way forward for Hsp90 inhibitors through the rational design of Hsp90 inhibitor combinations that may prevent and/or overcome resistance to Hsp90 inhibitors, providing an effective therapeutic strategy for KRAS-mutant NSCLC. [Read the Full Post]

Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer

0 | Jun 19 2017

Pappalardo F et al. showed a computational model able to simulate the main biochemical and metabolic interactions in the PI3K/AKT and MAPK pathways potentially involved in melanoma development. [Read the Full Post]

Inhibition of acquired-resistance hepatocellular carcinoma cell growth by combining sorafenib with phosphoinositide 3-kinase and rat sarcoma inhibitor

758 | Jun 15 2017

Wu CH et al. found that both inhibitors of PI3K/mTOR and RAS/ERK signaling are potentially effective antihepatocellular carcinoma drugs especially in treating sorafenib-resistant hepatocellular carcinoma. [Read the Full Post]

Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro

803 | Jun 13 2017

Qu Z et al. found the important role of HCC cell-derived exosomes in the drug resistance of liver cancer cells and demonstrate the intrinsic interaction between exosomes and their targeted tumor cells. [Read the Full Post]

miRNA-106a directly targeting RARB associates with the expression of Na(+)/I(-) symporter in thyroid cancer by regulating MAPK signaling pathway

850 | Jun 10 2017

Shen CT et al. provided new strategies for the diagnosis and treatment in radioiodine-refractory differentiated thyroid carcinoma. [Read the Full Post]

Interferon-Gamma and Fas Are Involved in Porphyromonas gingivalis-Induced Apoptosis of Human Extravillous Trophoblast-Derived HTR8/SVneo Cells via Extracellular Signal-Regulated Kinase 1/2 Pathway

1005 | May 30 2017

Ren H et al. demonstrated Pg induces IFN-γ secretion, Fas expression, and apoptosis in human extravillous trophoblast-derived HTR8/SVneo cells in an ERK1/2-dependent manner, and IFN-γ (explored by recombinant IFN-γ) and Fas are involved in Pg-induced apoptosis. [Read the Full Post]

Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells

0 | May 23 2017

Sponziello M et al. found that FN1 overexpression is an important determinant of thyroid cancer aggressiveness. [Read the Full Post]

Additive effects of low concentrations of estradiol-17β and progesterone on nitric oxide production by human vascular endothelial cells through shared signaling pathways

899 | May 21 2017

Pang Y et al. suggested that low doses of E2 and P4 may also have some beneficial cardiovascular effects in vivo when administered as hormone replacement therapy (HRT) for post-menopausal women. [Read the Full Post]

Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway

0 | May 19 2017

Mao J et al. highlighted that the secretion of IL-1β and STAT3 activation induced by Arsenic trioxide can be mediated by elevation of P38/JNK MAPK in HAPI microglia cells and then induced the toxicity of neurons. [Read the Full Post]

Neuritin Mediates Activity-Dependent Axonal Branch Formation in Part via FGF Signaling.

3056 | May 07 2017

Shimada T et al suggested that neuritin and FGF cooperate in inducing mossy fiber sprouting through FGF signaling. Together, these results suggest that FGF and neuritin-mediated axonal branch induction are involved in the aggravation of epilepsy. [Read the Full Post]

MEK-ERK inhibition potentiates WAY-600-induced anti-cancer efficiency in preclinical hepatocellular carcinoma (HCC) models

1181 | May 03 2017

Wang K et al demonstrated the potent anti-HCC activity by WAY-600, either alone or with MEK-ERK inhibitors. [Read the Full Post]

Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage-Induced Senescence Program in Gastric Cancer

0 | Apr 26 2017

Francica P et al. suggested that FOXM1 has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors. [Read the Full Post]

Urotensin II-induced insulin resistance is mediated by NADPH oxidase-derived reactive oxygen species in HepG2 cells

990 | Apr 22 2017

Li YY et al. found that UII induces insulin resistance, and this can be reversed by JNK inhibitor SP600125 and antioxidant/NADPH oxidase inhibitor apocynin targeting the insulin signaling pathway in HepG2 cells. [Read the Full Post]

P53 Is Involved in a Three-Dimensional Architecture-Mediated Decrease in Chemosensitivity in Colon Cancer

0 | Apr 20 2017

He J et al suggested that p53 is involved in a 3D architecture-mediated decrease in chemosensitivity to platinum in colon cancer. Mitogen-activated protein kinases (JNK1/2 and p38) do not play a dominant role in the mechanism. [Read the Full Post]

Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

0 | Apr 10 2017

Fu M et al indicated that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy. [Read the Full Post]

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

5999 | Apr 09 2017

Collectively, Wu C et al revealed, for the first time, a pivotal role of integrin signaling in regulation of RNA polymerase I transcriptional activity and shed light on the downstream signaling axis that participates in regulation of this key aspect of cell growth. [Read the Full Post]

Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation

2371 | Apr 03 2017

Huang A et al revealed a metabolic signature of sorafenib-resistant cells and suggests that glycolytic inhibition may override such resistance and warrant further clinical investigation. [Read the Full Post]

Small-Molecule Induction of Canine Embryonic Stem Cells Toward Naïve Pluripotency

738 | Mar 25 2017

Tobias IC et al. suggested that 2iL culture conditions promote the conversion of cESCs toward an epigenetically distinct pluripotent state resembling naïve PSCs. [Read the Full Post]

MITF depletion elevates expression levels of ERBB3 receptor and its cognate ligand NRG1-beta in melanoma

948 | Mar 24 2017

Alver TN et al. suggested that MITF may play a role in the development of acquired drug resistance through hyper-activation of the PI3K pathway. [Read the Full Post]

Icaritin activates JNK-dependent mPTP necrosis pathway in colorectal cancer cells

1109 | Feb 18 2017

Zhou C, et al.'s results showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. JNK-dependent mPTP necrosis pathway could be key mechanism responsible for ICT's actions. [Read the Full Post]

MEK Inhibition Sensitizes Precursor B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells to Dexamethasone through Modulation of mTOR Activity and Stimulation of Autophagy

0 | Feb 16 2017

Polak A et al. demonstrated that modulation of MEK/ERK pathway is an attractive therapeutic strategy overcoming GC resistance in B-ALL patients. [Read the Full Post]

Icaritin activates JNK-dependent mPTP necrosis pathway in colorectal cancer cells

1469 | Jan 08 2017

Zhou C, et al.‘s results showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. JNK-dependent mPTP necrosis pathway could be key mechanism responsible for ICT's actions. [Read the Full Post]

BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2

0 | Dec 24 2016

Zhang ZX et al. indicated that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis. [Read the Full Post]

Canonical FGFs Prevent Osteogenic Lineage Commitment and Differentiation of Human Bone Marrow Stromal Cells Via ERK1/2 Signaling

968 | Dec 19 2016

Simann M et al. presented new findings indicating that canonical FGFR-ERK1/2 signaling entrapped hBMSCs in a pre-committed state and arrested further maturation of committed precursors. [Read the Full Post]

BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts

1008 | Dec 18 2016

Kemper K et al.'s results illustrated the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients. [Read the Full Post]

TIMP-1 expression induced by IL-32 is mediated through activation of AP-1 signal pathway

1397 | Dec 07 2016

Xu H et al. believe that IL-32 might be involved in the pathogenesis of hepatic fibrosis by inducing TIMP-1 expression. [Read the Full Post]

Phosphorylation of the RNA-binding protein Dazl by MAPKAP kinase 2 regulates spermatogenesis

1323 | Dec 06 2016

The results of Williams PA et al. illuminate a novel role for MK2 in spermatogenesis, expand the repertoire of RNA-binding proteins phosphorylated by this kinase, and suggest that signaling by the p38-MK2 pathway is a negative regulator of spermatogenesis via phosphorylation of Dazl. [Read the Full Post]

BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2

1168 | Dec 03 2016

Zhang ZX et al. indicated that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis. [Read the Full Post]

Multiplexed Fluorescence Imaging of ERK and Akt Activities and Cell-cycle Progression

1126 | Nov 26 2016

Maryu G et al.'s study provides a useful tool for quantifying the dynamics among ERK and Akt activities and the cell cycle in a live cell, and for addressing the mechanisms underlying intrinsic resistance to molecularly targeted drugs. [Read the Full Post]

MEK inhibitor CI-1040 induces apoptosis in acute myeloid leukemia cells in vitro

998 | Nov 21 2016

Wei CR et al. demonstrated that CI-1040 induce apoptosis of U-937 cells and might be a new therapeutic option for the treatment of AML. [Read the Full Post]

Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4

1086 | Nov 20 2016

Zeng Q et al. provided critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4. [Read the Full Post]

Effects of bavachin and its regulation of melanin synthesis in A375 cells

1198 | Nov 18 2016

Bavachin inhibited the synthesis of melanin on A375 cells by inhibiting the protein and mRNA expression of TYR, TRP-1, TRP-2, ERK1, ERK2 andJNK2. [Read the Full Post]

The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer

1120 | Nov 18 2016

Beadnell TC et al. demonstrated that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single-agent inhibition. [Read the Full Post]

MEK Inhibition Sensitizes Precursor B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells to Dexamethasone through Modulation of mTOR Activity and Stimulation of Autophagy.

1222 | Nov 07 2016

Polak A, et al found that the data demonstrate that modulation of MEK/ERK pathway is an attractive therapeutic strategy overcoming GC resistance in B-ALL patients. [Read the Full Post]

Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage-Induced Senescence Program in Gastric Cancer

1195 | Oct 31 2016

FOXM1, a negative regulator of senescence, has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors. [Read the Full Post]

EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines

992 | Oct 26 2016

[Read the Full Post]

Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells

1140 | Oct 20 2016

Sponziello M et al. indicated that FN1 overexpression is an important determinant of thyroid cancer aggressiveness. [Read the Full Post]

Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway

1563 | Oct 17 2016

Mao J et al. highlighted that the secretion of IL-1β and STAT3 activation induced by Arsenic trioxide can be mediated by elevation of P38/JNK MAPK in HAPI microglia cells and then induced the toxicity of neurons. [Read the Full Post]

P53 Is Involved in a Three-Dimensional Architecture-Mediated Decrease in Chemosensitivity in Colon Cancer

1164 | Sep 21 2016

He J et al. suggested that p53 is involved in a 3D architecture-mediated decrease in chemosensitivity to platinum in colon cancer. [Read the Full Post]

Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

1357 | Sep 13 2016

Fu M, et al. found that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy. [Read the Full Post]

Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation

0 | Sep 08 2016

Huang A, et al. revealed a metabolic signature of sorafenib-resistant cells and suggests that glycolytic inhibition may override such resistance and warrant further clinical investigation. [Read the Full Post]

ERK induces degradation of tumor suppressor FBW7 in pancreatic cancer

6255 | Mar 18 2015

Ji et al. demonstrated a correlation between low expression of FBW7 and ERK activation in pancreatic cancer. [Read the Full Post]

αB-crystallin induces by matrix detachment via ERK is critical in inhibition of anoikis

6486 | Mar 05 2015

Malin et al. identified an matrix detachment-induced antiapoptotic molecular chaperone, αB-crystallin, confers anoikis resistance. [Read the Full Post]

The roles of physiological and synthetic IAP antagonism on c-IAP1/2 degradation

2795 | Mar 04 2015

Kocab et al. took a system approach to extensively compare the transcriptional programs triggered by CD30, which can degrade c-IAPs to SM-164, a synthetic IAP antagonist induces c-IAP degradation. [Read the Full Post]

Alternative functions of K-RAS in endocrine tumors

2161 | Jan 29 2015

Chamberlian et al. found K-RAS suppresses the growth in pancreatic endocrine cells, in contrast to its promoting effect on other cancer cells. [Read the Full Post]

MAPK cascade promotes early axonal degeneration in response to injury

4989 | Jan 21 2015

By using traumatic injury as a model, Yang et al. demonstrated a critical role of mitogen-activated protein kinase (MAPK) cascade in early axonal degeneration in response to injury. [Read the Full Post]

The important role of Cav1 in inducing peritoneal membrane epithelial-mesenchymal transition and fibrosis

2207 | Jan 13 2015

Strippoli et al. found Caveolin-1 (Cav1) acts as a critical factor in the increasing epithelial-mesenchymal transition (EMT), thickness, and fibrosis of peritoneum during peritoneal dialysis. [Read the Full Post]

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

9997 | Jan 07 2015

Winter et al. identified the underlying mechanism of the emerging JAK2 inhibitor therapy resistance in MPNs patients, and found the RAS and pathways mediated by AKT and ERK contribute to the resistance. [Read the Full Post]

The important role of immune microenvironment in resistance to MAPK pathway-targeted therapy

1834 | Jan 04 2015

Smith et al. demonstrated that the factors within immune microenvironment can promote the resistance to mitogen-activated protein kinase (MAPK) pathway-targeted therapy. [Read the Full Post]

Two states of BRAFV600 mutant melanoma that related to MAPK inhibition resistance

6100 | Dec 31 2014

Konieczkowski et al. revealed the mechanism of MAPK inhibition on BRAFV600 mutant melanomas. [Read the Full Post]

Novel approach of genetic perturbation

1977 | Dec 18 2014

Konermann et al. built a CRISPR-Cas9 complex for the regulation of effective transcriptional activation at target genomic loci. [Read the Full Post]

The early resistance to BARF(V600)-mutant melanoma is triggered by reactivation of MAPK pathway

2639 | Dec 12 2014

In regards to mechanism of emerging drug resistance, Long et al. demonstrated MAPK pathway was reactivated in early stage of resistance to combination therapy. [Read the Full Post]

ERK/Cdk5 axis regulates diabetes-related PPARγ phosphorylation

6771 | Nov 21 2014

Recently, Banks et al. discovered that ERK/Cdk5 axis is involved in regulation PPARγ activities, and the inhibition of ERK and MEK leads to the improvement of insulin resistance. [Read the Full Post]

The mechanism of drug resistance in BRAF (V600E) mutant melanoma

8242 | Nov 19 2014

Sun et al. demonstrated the resistance of BRAF (V600E) is reversible and adaptive. The process involves several transduction factors, such as EGFR, PDGFRB, TGF-β, and SOX10. [Read the Full Post]

PD0325901 is a potent MEK inhibitor that suppresses phosphorylation of ERK1

2068 | Mar 03 2014

PD0325901 (PD325901) is selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. [Read the Full Post]

RAF265 is a potent selective inhibitor of C Raf

2308 | Feb 21 2014

RAF265 shows 71% to 72% TVI% (tumor volume inhibition percentage) in HCT116 xenografts at 12 mg/kg. [Read the Full Post]

PLX4032 was able to reduce numbers of cancer cells

0 | Jan 21 2014

Vemurafenib is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM. [Read the Full Post]

SP600125 is a reversible ATP competitive inhibitor

2708 | Jan 14 2014

SP600125 is originally characterized as a selective ATP-competitive inhibitor of c-Jun N-terminal kinase JNK. [Read the Full Post]

VX 702 is A p38 MAP kinase inhibitor

2326 | Jan 09 2014

VX-702 is a highly selective inhibitor of p38α MAPK, 14-fold higher potency against the p38α versus p38β. [Read the Full Post]

AZD6244 is not competitive with ATP and inactivates the ERK1

2004 | Jan 07 2014

AZD6244 has little effects on the p38, c-Jun-NH2-kinase, phosphatidylinositol 3-kinase, and MEK5/ERK5 pathways. [Read the Full Post]

AZD6244 is a drug being investigated for the treatment of various types of cancer

0 | Dec 03 2013

AZD6244 is not competitive with ATP and inactivates the ERK1/2 phosphorylation with IC50 concentrations below 40 nM. [Read the Full Post]

PLX4032 was able to reduce numbers of cancer cells

2276 | Nov 20 2013

Vemurafenib (PLX4032, RG7204) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM. [Read the Full Post]

PD184352 is an inhibitor of mitogen activated protein kinase

2068 | Nov 19 2013

CI-1040 (PD 184352) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM, 100-fold more selective for MEK1/2 than MEK5. Phase 2. [Read the Full Post]

AZD6244 is a drug being investigated for the treatment of various types of cancer

2044 | Nov 15 2013

AZD6244 is not competitive with ATP and inactivates the ERK1/2 phosphorylation with IC50 concentrations below 40 nM. [Read the Full Post]

PD 0325901 is a selective and ATP non competitive MEK inhibitor

2102 | Nov 15 2013

PD0325901 (PD325901) is selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. Phase 1/2. [Read the Full Post]

RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors

2594 | Nov 06 2013

RAF265 inhibits C-Raf, wild type B-Raf and mutant (V600E) B-Raf. RAF265 effectively block phosphorylation of Raf's downstream substrates MEK and ERK in cells and also kill melanoma and colorectal cancer cell lines harboring B-Raf mutations independent of PTEN mutation status. [Read the Full Post]

PD0325901 is selective and non ATP competitive MEK inhibitor

2034 | Oct 17 2013

PF0325901 shows higher permeability than CI-1040, another MEK inhibitor. PD0325901 should be able to achieve higher systemic exposures than CI-1040. [Read the Full Post]

SB203580 is a selective inhibitor of p38 mitogen activated protein kinase

2999 | Oct 16 2013

SB203580 inhibits the IL-2-induced proliferation of primary human T cells, murine CT6 T cells, or BAF F7 B cells with an IC50 of 3–5 μm. [Read the Full Post]

U0126 is a highly selective inhibitor of both MEK1 and MEK2

0 | Oct 11 2013

U0126-EtOH functionally antagonizes AP- 1 transcriptional activity and blocks the production of a variety of cytokines and metalloproteinases involved in the inflammatory response. [Read the Full Post]

Sorafenib is used to treat advanced renal cell carcinoma

2340 | Sep 22 2013

Sorafenib tosylate inhibits both wild-type and V599E mutant B-Raf activity with IC50 of 22 nM and 38 nM, respectively. [Read the Full Post]

PLX4032 is a highly selective inhibitor of BRAF kinase activity

2430 | Sep 05 2013

PLX4032 is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM. [Read the Full Post]

U0126 is a highly selective inhibitor of both MEK1 and MEK2

2262 | Aug 02 2013

U0126-EtOH functionally antagonizes AP- 1 transcriptional activity and blocks the production of a variety of cytokines and metalloproteinases involved in the inflammatory response. [Read the Full Post]

Trametinib had good results for V600E mutated metastatic melanoma

2332 | Jul 25 2013

GSK1120212 inhibits the phosphorylation of MBP regardless of the isotype of Raf and MEK, with IC50 ranging from 0.92 nM to 3.4 nM. GSK1120212 demonstrates no inhibition of the kinase activities of c-Raf, B-Raf, ERK1 and ERK2. [Read the Full Post]

Selumetinib is a drug being investigated for the treatment of various types of cancer

1986 | May 08 2013

AZD6244 also inhibits the growth of primary HCC cells through inhibition of ERK1/2 and p90RSK phosphorylation, accompanied with elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. [Read the Full Post]

SP600125 is supplied as a lyophilized powder

2869 | Apr 26 2013

SP600125 is originally characterized as a selective ATP-competitive inhibitor of c-Jun N-terminal kinase JNK. In Jurkat T cells, SP600125 inhibits the phosphorylation of c-Jun with IC50 of 5 μM to 10 μM. [Read the Full Post]

PD98059 is a potent and selective inhibitor of MAP kinase

2002 | Apr 10 2013

PD98059 inhibits either basal MEK1 or a partially activated MEK produced by mutation of serine at residues 218 and 222 to glutamate (MEK-2E) with IC50 of 2 μM. PD98059 does not inhibit the MAPK homologues JNK and P38. PD98059 is highly selective against MEK, as it does not inhibit a number of other kinase activities including Raf kinase, cAMP-dependent kinase, protein kinase C, v-Src, epidermal growth factor (EGF) receptor kinase, insulin receptor kinase, PDGF receptor kinase, and phosphatidylinositol 3-kinase. [Read the Full Post]

PD98059 is a non ATP competitive MEK inhibitor with IC50

2079 | Mar 27 2013

PD98059 inhibits either basal MEK1 or a partially activated MEK produced by mutation of serine at residues 218 and 222 to glutamate (MEK-2E) with IC50 of 2 μM. PD98059 does not inhibit the MAPK homologues JNK and P38. [Read the Full Post]

MEK inhibition in BRAF mutated melanoma

1935 | Dec 24 2012

Systemic efforts to decipher the molecular mechanisms MEK inhibition of these actions led to the isolation of the mTOR protein and the identification of two multimolecular complexes that are formed bymTOR [Read the Full Post]

MEK PATHWAY INHIBITION FOR CANCER THERAPY

2410 | Aug 13 2012

SIGNALLING OF MEK PATHWAY: Various types of cells exist on the surface of the cells helping the cells to coordinate with the environment and the other cells. The growth factor receptors are such receptors which after getting triggered by the ligands usually play a very vital role in the process of cell signaling hence stimulate different pathways that are necessary for the cell survival and growth. One such example is MEK kinase cascade that plays an important role in pro-survival signaling. The inhibition of MEK kinase pathway is one of the attractive strategies when there is a need to inhibit un-necessary proliferation of cells in case of cancer. It has been studied that MEK signaling pathway gets hyperactivated in the cancer cells, so scientists devised a good therapeutic tool against cancer by designing different inhibitors of MEK pathway. 20 years ago, the structural properties of MEK molecule were described [1], which make the approach of scientists much easier for specific MAP2k2 inhibitor. [Read the Full Post]

MEK INHIBITOR AGAINST UNCONTROLLED GROWTH OF CELLS

2682 | Aug 07 2012

MEK – RECEPTORS: Growth factor receptor is found on the surface of cells and upon stimulation a protein is encoded in the nucleus which is vital for cell signaling. A type of kinases is called MEK that is important for the pro-survival signaling. An easy approach to hinder or control the pro-survival signaling is the inhibition of MEK which can be done by designing MEK kinase inhibitor. The most suitable example of is of cancer cells which is characterized by uncontrolled cell proliferation and in these cells MEK signaling pathway is found as hyperactivated, hence the introduction of MEK pathway inhibitors is the appropriate therapy. About 20 years back the structure of MEK was elucidated, due to this researcher are aided well for the development of specific MEK inhibitors. [Read the Full Post]

B-RAF INHIBITOR FOR TUMORS

2246 | Apr 23 2012

V600E MUTATION AND B-RAF PATHWAY: B-Raf, a proto-oncogene is a serine/threonine kinase protein playing a major role in different signalling cascades which regulates cell growth and this B-Raf proto-oncogene in humans is encoded by B-RAF gene. B-Raf is found to be affecting the processes of cell division and cell differentiation by playing a regulatory role in ERK and MAPK signaling cascades. Any sort of acquired mutation in this gene leads to abnormalities in related signaling cascades as a result uncontrolled cell division and growth which leads to cancer eventually while an inherited mutation was found to be linked with cardiofaciocutaneous syndrome which is a birth defect. For this reason the use of BRaf inhibitor for the inhibition of B-Raf pathways is found to be a valuable and attractive approach. More than thirty mutations found to be clustered in activation and flanking regions of B-Raf gene and they were analyzed as well. It was observed that substitution of Valine with Glutamic acid at codon number 600 is very abundant, clinically relevant and most famous one and this mutation (V6000E) is targeted the most as compared to B-Raf selective inhibitor. [Read the Full Post]

PLX4032 – THE B-RAF ANTAGONIST

2098 | Mar 19 2012

Introduction: The Effect of B-Raf mutation Cellular pathways are sequences of chemical reactions that take place in the cell membrane, cytosole and the nucleus to initiate, control or regulate processes necessary for normal function. A protein called RAS is anchored in the cell membrane and upon activation with GTP can bind to another protein called RAF [1]. With transfer of a phosphate group from GTP the RAF protein becomes detached and activated. Moving through the cytosole start the signal of RAF is passed on to MEK and then to ERK by means of phosphorylation. Eventually the signal reaches the cell nucleus and growth processes are started depending on the original signal. Therefore, it can be seen that Raf and MEK are two proteins whose major function is to carry a signal from membrane to nucleus to ensure cell survival. Any form of deviation from the normal situation in regards to these two proteins would cause significant problems. With regards to Raf three isoforms have been isolated and characterized known as A,B or C-Raf. [Read the Full Post]

PD98059 – THE MOST COMMON MEK INHIBITOR

2926 | Mar 20 2012

Introduction: The Mitogen-Activated Protein Kinase Protein kinases are responsible for much of the activation, control and regulation of the cell cycle processes, such activities as cell division, cell migration, gene transcription and apoptosis. Typical a kinase cascade exists where a trans membrane kinase is activated by an extra cellular factor such as growth factors, mitogens, stress factors and cytokines. The top level of the MAP kinases are referred to as MAP kinase kinase kinases and examples are the Raf series of proteins, MLK3, TAK, MEKK1, 2,3 &4 which trigger signaling cascades down to the next level of proteins usually located either bonded to the inner membrane or in the cell cytosole. Second level kinases examples are MEK1/2 or 5, MKK3/4 or 6/7. The last level MAP kinases are usually located in the mitochondria / nucleus membranes or in either the mitochondria / nucleus themselves. The extensive nature of the MAPK pathways means that they are significantly involved in the normal and abnormal growth patterns of the mammalian system. [Read the Full Post]

AZD6244 – INHIBITNG MEK

2378 | Mar 18 2012

The Inhibition of MEK MEK (also known as MAPK) is part of a pathway the links the extracellular signals to the nucleus and consists of RAS, a tyrosine kinase protein attached inter-cellularly to the membrane. RAF, a cytosolic protein which shifts to the membrane under the influence of activated RAS, MEK a cytosolic protein that is activated by the action of a phosphorylated RAF, it has a highly specific activity for ERK ( the last member of the pathway, located in the nucleus and active in gene transcription, cellular growth and cell cycle regulation. The interesting fact is the Raf and Erk both can have one of multiple targets but MEK is dedicated to Erk only. This high degree of specificity means that MEK is a prime target for inhibition and the subsequent interference in this pathway. The RAS – ERK pathway has been investigated thoroughly in both normal and tumor tissues where it has been found that in numerous tumor tissues this pathway is over expressed. [Read the Full Post]

PD0325901 – SUCCESS OF A MEK INHIBITOR

3105 | Mar 19 2012

Introduction: MEK inhibition In numerous tumors investigates for kinase activity one of the key pathways to stand out is the RAS / RAF pathway. With mutations of both RAS (KRAS) and RAF (BRafV600E) demonstrating significant resistance in chemotherapeutic action for EGFR, RAS and RAF inhibitors, a target further down the signaling pathway was thought to be a possible side step to this resistance. EGFR is a transmembrane protein which passes a signal (via phosphorylation) to an internal membrane bound protein (GRBS and SOS). This signal is passed down stream via RAS and RAF to a nexus point, MEK. This protein is the target of several pathway crossovers and while MEK itself has not been shown to be mutated; it is recipient of signals from several proteins that are. Signaling via MEK can lead to several different functions in the cell include cell growth, proliferation and migration. [Read the Full Post]

MEK INHIBITOR AGAINST SUSTAINED GROWTH OF CELLS

2180 | Mar 19 2012

Introduction: The RAS-Raf-MEK-MAPK pathway One of the pathways researched in relation to cancerous properties is that of the RAS-Raf –MEK-MAPK phosphorylation signaling cascade. This pathway has been linked with the regulation of gene transcription via the nucleus receptor MAPK. The pathway is initiated via transmembrane receptor proteins such as EDGR, VEGFR, PDGFR or IGFR which receives an extracellular signal via ligand binding which is translated into the phosphorylation of the membrane bound protein RAS via the exchange of GDP for GTP in the complex receptor protein SOS and GRB2. RAS is the description of a family of proteins with a signature binding domain they are located in the intracellular side to the cell membrane. [Read the Full Post]

B-RAF INHIBITOR AGAINST CANCERS

3097 | Mar 13 2012

The mechanism of the RAS-Raf pathway In the normal situation cells will live and die on a regular basis, maintaining healthy tissue and organs. To control this process there are several signaling pathway which either stimulate the cell to proliferate or induce the normal sequence of events for cell death (Apoptosis). The pathway which controls cell proliferation, cell differentiation and cell growth is the RAS/Raf/MEK/Erk pathway Growth is initiated by the activation of RAS, which is located in the plasma membrane, by activation of its tyrosine kinase receptor by extracellular growth factors. The RAS protein receptors are on the external face of the cell while signal is conducted inside the cell. Growth factors activate the external RAS protein so the internal root of the RAS protein complexes with Raf proteins activating them. The raf proteins then actively phosphorylates the MEK protein which in turn phosphorylates the Erl protein and cell division /proliferation beginnings. The role of Raf is therefore to carry the signal from the activated RAS and to MEK protein in the cytosole/nuclease to initiate proliferation activity, the signal also acts as a cell survival mechanism. [Read the Full Post]

JNK, a potential therapeutic target for the treatment of nephrotoxicity

3305 | Nov 14 2011

Nephrotoxicity is a poisonous effect of some substances, including toxic chemicals and medication, on the kidneys, and cyclosporine (CsA) nephrotoxicity is one kind of nephrotoxicity. It is reported that the epithelial to mesenchymal transition(EMT) is an important mechanism contributing to the pathogenesis of cyclosporine (CsA) nephrotoxicity by promoting the generation of myofibroblasts. Some studies suggested that he endoplasmic reticulum (ER) stress as a potential mechanism may participate in the modulation of tubular cell plasticity in CsA-induced EPCs[1]. However, the precise mechanisms have not been known. [Read the Full Post]

Raf kinases, the excellent molecular targets for anticancer therapy

3133 | Oct 31 2011

Raf kinases are a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes. Raf kinases mainly contain three mammalian RAF proteins (A, B and CRAF) and participate in the RAS-RAF-MEK-ERK signal pathways. Of which, B-Raf is the family member most easily activated by Ras, and the kinase activity of B-Raf is higher than that of C-Raf and, likely, A-Raf. Thus, the frequent mutational activation of BRAF is often observed in human tumors, but not CRAF or ARAF. [Read the Full Post]

Sorafenib, a potential therapy for Chronic lymphocytic leukemia patients

2537 | Oct 13 2011

Chronic lymphocytic leukemia (CLL) is a common leukemia which causes a slow increase in white blood cells called B lymphocytes, or B cells. This cancer mostly affects adults, around age 70, and leads to approximately 5000 deaths annually. The frontline therapy for CLL mainly use several chemotherapy drugs alone or in combination, such as Fludarabine, chlorambucil, cyclophosphamide, and rituximab. Besides, bone marrow or stem cell transplantation may be used in younger patients with advanced or high-risk CLL. [Read the Full Post]

p38 MAPK inhibitor, FR167653, a potent therapy against PTHrP-induced osteoclastogenesis and bone resorption-related diseases

3113 | Sep 07 2011

Study on mechanism indecates that PTHrP stimulates osteoclastogenesis by increasing receptor activator of NF-kB ligand (RANKL) expression. p38 MAPK is required for osteoclast differentiation. This implies the existence of relationship between p38 MAPK and PTHrP in osteoclastogenesis. [Read the Full Post]

Dietrich, J., V. Gokhale, et al. (2010). "Application of a novel [3+2] cycloaddition reaction to prepare substituted imidazoles and their use in the design of potent DFG-out allosteric B-Raf inhibitors." Bioorg Med Chem 18(1): 292-304.

2575 | Jul 15 2011

An article about drug discovery of b-raf inhibitor design and molecular modeling. [Read the Full Post]

Munoz, L. and A. J. Ammit (2010). "Targeting p38 MAPK pathway for the treatment of Alzheimer

2578 | Jul 14 2011

This is an introduction of the relationship between p38 MAPK and Alzheimer's disease because p38 MAPK plays an important role in Alzheimer's disease. It also list the p38 MAPK inhibitors Alzheimer's disease patients could benefit from. [Read the Full Post]

Wong, K. K. (2009). "Recent developments in anti-cancer agents targeting the Ras/Raf/ MEK/ERK pathway." Recent Pat Anticancer Drug Discov 4(1): 28-35.

2287 | Jul 12 2011

Give an introduction of inhibitors targeting the Ras/Raf/ MEK/ERK pathway. This article summaries the current and future development of anti-cancer drugs or inhibitors of Ras/Raf/ MEK/ERK pathway and the difference between those drugs or inhibitors. [Read the Full Post]

Roux, P. P. and J. Blenis (2004). "ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions." Microbiol Mol Biol Rev 68(2): 320-344.

2923 | Apr 9 2011

Give a introduction of physiological functions of ERK and P38 MAPK. [Read the Full Post]

Hagemann, C. and J. L. Blank (2001). "The ups and downs of MEK kinase interactions." Cell Signal 13(12): 863-875.

2255 | Mar 18 2011

A review focus on MEK. This review summarises the upstream and downstream of MEK. It give a detail introduction of the targets which interact with MEK. [Read the Full Post]

Davis, R. J. (2000). "Signal transduction by the JNK group of MAP kinases." Cell 103(2): 239-252.

3880 | Mar 9 2011

This is an classic review which introduce role of the JNK Signaling Pathway in MAPKKK pathway, cell survival and apoptosis. [Read the Full Post]