Opportunities and challenges of targeting c-Met in the treatment of digestive tumors

Abstract

At present, a large number of studies have demonstrated that c-Met generally exerts a crucial function of promoting tumor cells proliferation and differentiation in digestive system tumors. c-Met also mediates tumor progression and drug resistance by signaling interactions with other oncogenic molecules and then activating downstream pathways. Therefore, c-Met is a promising target for the treatment of digestive system tumors. Many anti-tumor therapies targeting c-Met (tyrosine kinase inhibitors, monoclonal antibodies, and adoptive immunotherapy) have been developed in treating digestive system tumors. Some drugs have been successfully applied to clinic, but most of them are defective due to their efficacy and complications. In order to promote the clinical application of targeting c-Met drugs in digestive system tumors, it is necessary to further explore the mechanism of c-Met action in digestive system tumors and optimize the anti-tumor treatment of targeting c-Met drugs. Through reading a large number of literatures, the author systematically reviewed the biological functions and molecular mechanisms of c-Met associated with tumor and summarized the current status of targeting c-Met in the treatment of digestive system tumors so as to provide new ideas for the treatment of digestive system tumors.

Gap junction beta‐4 accelerates cell cycle progression and metastasis through MET–AKT activation in pancreatic cancer

“…We hypothesized that GJB4 activates the MET signaling pathway, then induces cell cycle progression and upregulates metastatic properties in pancreatic cancer cells. AKT, which is recognized as a downstream target molecule of MET, is a positive regulator of the cell cycle, and of migration/invasion 15,24 . Additionally, Src has been identified to be involved in the MET signaling pathway in lung adenocarcinoma 10 .…”

“…Except for mutated GJB4, which has been identified as the causative gene for erythrokeratodermia variabilis et progressiva, the roles and signaling pathways of GJB4 have not been completely As reported here, MET has emerged as a therapeutic target for patients with pancreatic cancer. 15 Selective MET inhibitors, such as tepotinib and capmatinib that are successful as cancer therapeutics, have been approved for patients harboring a MET exon 14 skipping mutation in non-small-cell lung cancer. 25,26 Regarding pancreatic cancer, Li et al found that MET is a bona fide pancreatic cancerspecific receptor tyrosine kinase through comprehensive analyses and that high MET expression is related to a worse prognosis.…”

“…Therefore, the HGF–MET pathway is an attractive target for therapeutics for this cancer 14 . However, clinical trials for this pathway in pancreatic cancer have not yet shown effective antitumor activities 15 . This underscores the need to explore alternative modes of action of the HGF–MET pathway to develop therapeutics for MET‐driven pancreatic cancer.…”

Targeting c-Met in the treatment of urologic neoplasms: Current status and challenges

“…C-Met interacts with other oncogenic molecules (such as EGFR and RON) to activate downstream pathways, thereby mediating tumor progression and drug resistance ( 69 ). Similarly, there is also signal interaction between c-Met and VEGF and RON molecules in urologic neoplasms ( 40 , 56 ).…”

“…This study is the first to demonstrate the efficacy of combining c-Met inhibition with ionizing radiation in the treatment of hormone-independent PCa. In addition, c-Met was found to be abnormally activated in the absence of HGF in many solid tumors (69). Y. Dai et al (63) studied the reaction of PC-3 cells against HGF neutralizing antibody or small molecule c-Met kinase inhibitor (BMS-777607).…”