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Blog of Signaling Pathways

Oncogenic enhancer of zeste homolog 2 is an actionable target in patients with non-small cell lung cancer

57 views | Sep 02 2019

Shi B et al. showed that overexpression of EZH2 is a negative prognostic indicator. Increased EZH2 expression predicts for response to HDAC inhibitors and thus could serve as a biomarker for selecting NSCLC patients for treatment with HDAC inhibitors. [Read the Full Post]

Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas

22 views | 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

19 views | 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]

NK2 receptor mediated detrusor muscle contraction involves Gq/11-dependent activation of voltage-dependent calcium channels and the RhoA-Rho kinase pathway

57 views | Aug 30 2019

Dér B et al. identified potential therapeutic targets of bladder dysfunctions related to upregulation of TKs. [Read the Full Post]

PARP Inhibition Suppresses GR-MYCN-CDK5-RB1-E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer

32 views | Aug 30 2019

Liu B et al. demonstrated efficacy for OLA+DINA combination therapy in NEPC xenograft models. [Read the Full Post]

Functional genomics identifies predictive markers and clinically actionable resistance mechanisms to CDK4/6 inhibition in bladder cancer

33 views | Aug 29 2019

Tong Z et al. found that identification of potential predictive markers, resistance mechanisms and rational combination therapies could be achieved by applying a CRISPR-dCas9 screening approach in bladder cancer. [Read the Full Post]

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

42 views | 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]

XPO1 inhibitor KPT-330 synergizes with Bcl-xL inhibitor to induce cancer cell apoptosis by perturbing rRNA processing and Mcl-1 protein synthesis

23 views | Aug 28 2019

Zhu ZC et al. clarify the reason of apoptosis resistance of cancer cells to XPO1 inhibition and develop a potential strategy for treating solid tumors. [Read the Full Post]

Blocking EZH2 methylation transferase activity by GSK126 decreases stem cell-like myeloma cells

0 views | Aug 27 2019

Zeng D et al. suggested that EZH2 inactivation by GSK126 is effective in killing MM cells and CSCs as a single agent or in combination with bortezomib. Clinical trial of GSK126in patients with MM may be warranted. [Read the Full Post]

The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients

31 views | Aug 27 2019

Kennedy ME indicated the human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials. [Read the Full Post]

Treatment of γ-Hydroxybutyric Acid and γ-Butyrolactone Overdose with Two Potent Monocarboxylate Transporter 1 Inhibitors, AZD3965 and AR-C155858

28 views | Aug 26 2019

Follman KE et al. indicated that inhibition of MCT1 is an effective treatment of GHB/GBL overdose. [Read the Full Post]

Effects of EF-24, RAD001, and paclitaxel on the expression profiles of apoptotic and anti-apoptotic genes

0 views | Aug 26 2019

Alp E et al. showed that response of these cells to paclitaxel, EF-24, and RAD001 was found different at the transcriptional level of apoptotic and antiapoptotic genes. Therefore, understanding transcriptional changes after these drug exposure may give us a change to figure out more realistic results of the apoptotic pathway inhibition. [Read the Full Post]

Metformin and 4SC-202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma

92 views | Aug 25 2019

He Y et al. revealed that ΔNp63 mediated anticancer effects of metformin and 4SC-202, as overexpression or suppression of ΔNp63 could attenuate or facilitate the apoptosis rate of OSCC under metformin or/and 4SC-202 treatment. Collectively, metformin and 4SC-202 synergistically promote intrinsic apoptosis through accelerating ubiquitin-mediated degradation of ΔNp63 in OSCC, and this co-treatment can serve as a potential therapeutic scheme for OSCC. [Read the Full Post]

Proteasome inhibitor PS-341 limits macrophage necroptosis by promoting cIAPs-mediated inhibition of RIP1 and RIP3 activation

35 views | Aug 25 2019

Zhang Y et al. identified a new role of PS-341 in the cell death of BMDMs and provided a novel insight into the atherosclerotic inflammation caused by proteasome-mediated macrophage necroptosis. [Read the Full Post]

Inhibition of glioblastoma dispersal by the MEK inhibitor PD0325901

26 views | 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]

Alisertib demonstrates significant antitumor activity in bevacizumab resistant, patient derived orthotopic models of glioblastoma

39 views | Aug 20 2019

Kurokawa C et al. showed that alisertibdisplays significant antitumor activity against primary GBM lines and xenografts, including patient derived GBM lines resistant to bevacizumab; these data support clinical translation in GBM. [Read the Full Post]

Selective BCL-XL inhibition promotes apoptosis in combination with MLN8237 in medulloblastoma and pediatric glioblastoma cells

39 views | Aug 20 2019

Levesley J et al. indicated that selective small-molecule inhibitors of BCL-XL may enhance the efficacy of MLN8237 and other targeted chemotherapeutic agents. [Read the Full Post]

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

0 views | Aug 19 2019

Chen YN et al. demonstrated that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers. [Read the Full Post]

Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma

34 views | Aug 19 2019

Knutson SK et al. indicated these data confirm the dependency of EZH2-mutant NHL on EZH2 activity and portend the utility of EPZ-6438 as a potential treatment for these genetically defined cancers. [Read the Full Post]

Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations

58 views | Aug 18 2019

Davis RB et al. showed that two gamma secretase inhibitors (GSIs), DAPT (GSI-IX) and RO4929097, cause dose-dependent inhibition of Notch target gene expression (Hey1) and rate of migration of monolayer cultures of lymphatic endothelial cells (hLECs) and blood endothelial cells (HUVEC). GSIs also inhibit HUVEC network formation. hLECs are more sensitive to GSIs compared to HUVEC. GSIs have been found to be safe in clinical trials in patients with Alzheimer's disease or cancer. Our results provide further rationale to support testing of Notch inhibitors in patients with extracranial vascular malformations. [Read the Full Post]