Targeting c‐MET by LY2801653 for treatment of cholangiocarcinoma

Abstract

Palliative treatment options for human cholangiocarcinoma (CCC) are quite limited and new therapeutic strategies are of utmost need. c-MET has been shown to be deregulated in many cancers, but the role of c-MET in the carcinogenesis of CCC remains unclear. The main purpose of this study is to evaluate the expression and also to investigate the role of c-MET and its effective inhibition for the treatment of CCC. In this study we investigated the effects of LY2801653, a small-molecule inhibitor with potent activity against MET kinase, in human CCC cell lines and in vivo using a xenograft mouse model. We have investigated the role of c-MET and its inhibitory effects on migration, invasion, colony formation, MET downstream targets, and CCC tumor growth. We also analyzed the role of apoptosis and senescence as well as the influence of hypoxia in this context. c-MET and p-MET were expressed in 72% and 12.5% of human CCC tissues and in TFK-1, SZ-1 cell lines. MET inhibition was achieved by blocking phosphorylation of MET with LY2801653 and subsequent down regulation of c-MET downstream targets. Treatment showed in a xenograft model potent anti-tumor activity. LY2801653 is an effective inhibitor and suppress the proliferation of CCC cells as well as the growth of xenograft tumors. Therefore, inhibition of c-MET could be a possible alternative approach for the treatment of human CCC. © 2016 Wiley Periodicals, Inc.

Neuropilin‐1 regulated by miR‐320 contributes to the growth and metastasis of cholangiocarcinoma cells

“…The latter inhibits the activity of CDK2/cyclin E complex, thus blocking cell cycle progression . The EGF/EGFR pathway co‐activated by NRP‐1 increases the phosphorylation of MEK and ERK, which promotes the proliferation and metastasis of CCA cells . Although not investigated in the present study, the cross‐talks among the above signalling pathways may also contribute to the proliferation and metastasis of cancer cells …”

Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis

“…C-MET is the receptor of HGF and is widely expressed in various types of cancer. The HGF-cMET pathway is involved in cell invasion, proliferation and angiogenesis, and is believed to be a novel target for cancer therapy1819. Gastric cancer (GC) with liver metastasis is one of the main forms in advanced GC2021; however, the molecular mechanism in this process remains unclear.…”

Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma

“…Of these two agents, LY2801653 is a type II kinase inhibitor with cMET as one of its target and displays anti-tumor activity in non-small cell lung carcinoma and cholangiocarcinoma preclinical models (32–34). LY2875358 is a neutralizing and internalizing anti-cMET bivalent antibody that showed potent anti-tumor activity in both HGF-dependent and cMET amplified preclinical tumor models (35).…”