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Blog of Signaling Pathways

CCI-779 (Temsirolimus) exhibits increased anti-tumor activity in low EGFR expressing HNSCC cell lines and is effective in cells with acquired resistance to cisplatin or cetuximab

65 views | May 27 2019

Niehr F et al. indicated that activity of CCI-779 in HNSCC cells harboring TP53 mutations and displaying a phenotype of cisplatin resistance suggests its clinical potential even in patients with dismal outcome after current standard treatment. Cetuximab/mTORi combinations might be useful for treatment of tumors with high expression of EGFR/p-EGFR and/or acquired cetuximab resistance. This combinatorial treatment modality needs further evaluation in future translational and clinical studies. [Read the Full Post]

Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib

146 views | May 26 2019

Vyse S et al. provided a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance. [Read the Full Post]

Hemin-induced platelet activation and ferroptosis is mediated through ROS-driven proteasomal activity and inflammasome activation: Protection by Melatonin

68 views | May 26 2019

NaveenKumar SK et al. demonstrated an association of platelet activation/ferroptosis with proteasome activity and inflammasome activation. Although, high-throughput screening has recognized ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) as potent ferroptosis inhibitors, having an endogenous antioxidant such as MLT as ferroptosis inhibitor is of high interest. MLT is a well-known chronobiotic hormone that regulates the circadian rhythms in vertebrates. It is also known to exhibit potent antioxidant and ROS quenching capabilities. MLT can regulate fundamental cellular functions by exhibiting cytoprotective, oncostatic, antiaging, anti-venom, and immunomodulatory activities. The ROS scavenging capacity of MLT is key for its cytoprotective and anti-apoptotic properties. Considering the anti-ferroptotic and anti-apoptotic potentials MLT, it could be a promising clinical application to treat hemolytic, thrombotic and thrombocytopenic conditions. Therefore, we propose MLT as a pharmacological and therapeutic agent to inhibit ferroptosis and platelet activation. [Read the Full Post]

A Preclinical Model for Studying Herpes Simplex Virus Infection

0 views | May 25 2019

Tajpara P et al. present a previously unreported ex vivo HSV-1 infection model with abdominal human skin to test antiviral drugs, thus bridging the gap between in vitro and in vivo drug screening and providing a valuable preclinical platform for HSV research. [Read the Full Post]

Midostaurin/PKC412 for the treatment of newly diagnosed FLT3 mutation-positive acute myeloid leukemia

121 views | May 25 2019

Luskin MR et al. indicated that expert commentary: The approval of midostaurin represents the first new therapy for AML in several decades. It is also the first targeted therapy approved for AML. Future studies will focus on defining mechanisms of resistance to midostaurin as well as establishing the role of midostaurin in combination with hypomethylating agents and as maintenance therapy. Second generation, more potent and selective FLT3 inhibitors are also in development; these agents need to be compared to midostaurin. [Read the Full Post]

Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis

76 views | May 24 2019

Chen G et al. provided a novel therapeutic strategy to optimize MK-1775 treatment efficiency in lung cancers. [Read the Full Post]

A novel anti-melanoma SRC-family kinase inhibitor.

83 views | 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]

AMP-activated protein kinase (AMPK) activator A-769662 increases intracellular calcium and ATP release from astrocytes in an AMPK-independent manner

136 views | May 23 2019

Vlachaki Walker JM et al. indicated that AMPK is required to maintain basal eATP levels but is not required for A-769662-induced increases in eATP. A-769662 (>50 μM) enhanced intracellular calcium levels leading to ATP release in an AMPK and purinergic receptor independent pathway. [Read the Full Post]

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

0 views | 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]

Tipifarnib prevents development of hypoxia-induced pulmonary hypertension

66 views | May 22 2019

Duluc L et al. demonstrated the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension. [Read the Full Post]

Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial

145 views | May 21 2019

Rummel M et al. indicated that in combination with rituximab, bendamustine was more effective than fludarabine, suggesting that bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle-cell lymphomas. [Read the Full Post]

Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives

110 views | May 21 2019

Shagufta et al. anticipated that it will assist medicinal chemists in the synthesis of novel and pharmacologically potent agents for various therapeutic targets. [Read the Full Post]

Targeted blockade of HSP90 impairs DNA-damage response proteins and increases the sensitivity of ovarian carcinoma cells to PARP inhibition

111 views | May 19 2019

Gabbasov R et al. suggested that HSP90 inhibition has the potential to sensitize some HGSOC patients without HR pathway alterations to PARPi, and potentially other DNA-damage inducing agents. [Read the Full Post]

Clinical efficacy of daratumumab, pomalidomide, and dexamethasone in patients with relapsed or refractory myeloma: Utility of re-treatment with daratumumab among refractory patients

30 views | May 19 2019

Nooka AK et al. highlighted the fact that the introduction of monoclonal antibody combination strategies and IMiDs as earlier lines of therapeutic options potentially could deliver better clinical outcomes. [Read the Full Post]

Low-intensity pulsed ultrasound promotes the proliferation of human bone mesenchymal stem cells by activating PI3K/AKt signaling pathways

122 views | May 18 2019

Xie S et al. suggested that LIPUS exposure may be involved in the proliferation of hBMSCs via activation of the PI3K/AKt signaling pathway and high expression of cyclin D1, and the intensity of 50 or 60 mW/cm2 and exposure time of 5 minutes were determined to be the optimal parameters for LIPUS exposure. [Read the Full Post]

Hydroxysafflor yellow A inhibited lipopolysaccharide-induced non-small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways

75 views | May 18 2019

HYSA suppressed LPS-mediated proliferation, migration, invasion, and EMT in A549 and H1299 cells by inhibiting the PI3K/Akt/mTOR and ERK/MAPK signaling pathways, indicating that HYSA may be a potential candidate to treat inflammation-mediated NSCLC. [Read the Full Post]

Inhibition of apoptosis by caspase inhibitor Z-VAD-FMK improves cryotolerance of in vitro derived bovine embryos

100 views | May 17 2019

Pero ME et al. found that the addition of 20 μM Z-VAD-FMK during vitrification/warming and post-warming culture partially inhibits cryopreservation-induced apoptosis by reducing the level of active caspase 3, suggesting a potential use as an additive to ameliorate the efficiency of embryo cryopreservation in cattle, critical for a further diffusion of IVEP technology in the field. [Read the Full Post]

Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway.

118 views | May 17 2019

Herbertz S et al. summarized the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients. [Read the Full Post]

First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma

115 views | May 16 2019

On the basis of the safety, pharmacokinetics, and antitumor activity in patients with glioma, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation. [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

58 views | 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]