Editorial
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. May 26, 2015; 6(2): 16-27
Published online May 26, 2015. doi: 10.4331/wjbc.v6.i2.16
Promise and challenges on the horizon of MET-targeted cancer therapeutics
Yu-Wen Zhang
Yu-Wen Zhang, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, United States
Author contributions: Zhang YW solely contributed to this manuscript.
Conflict-of-interest: There is no potential conflict of interest relevant to this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yu-Wen Zhang, MD, PhD, Center for Cancer and Cell Biology, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, United States. yuwen.zhang@vai.org
Telephone: +1-616-2345532 Fax: +1-616-2345533
Received: January 20, 2015
Peer-review started: January 20, 2015
First decision: February 7, 2015
Revised: April 8, 2015
Accepted: April 16, 2015
Article in press: April 18, 2015
Published online: May 26, 2015
Processing time: 121 Days and 13.4 Hours
Abstract

MET (MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand, hepatocyte growth factor (HGF), eliciting its diverse biological activities that are crucial for development and physiology. Alteration of the HGF-MET axis results in inappropriate activation of a cascade of intracellular signaling pathways that contributes to hallmark cancer events including deregulated cell proliferation and survival, angiogenesis, invasion, and metastasis. Aberrant MET activation results from autocrine or paracrine mechanisms due to overexpression of HGF and/or MET or from a ligand-independent mechanism caused by activating mutations or amplification of MET. The literature provides compelling evidence for the role of MET signaling in cancer development and progression. The finding that cancer cells often use MET activation to escape therapies targeting other pathways strengthens the argument for MET-targeted therapeutics. Diverse strategies have been explored to deactivate MET signaling, and compounds and biologics targeting the MET pathway are in clinical development. Despite promising results from various clinical trials, we are still waiting for true MET-targeted therapeutics in the clinic. This review will explore recent progress and hurdles in the pursuit of MET-targeted cancer drugs and discuss the challenges in such development.

Keywords: MET; Hepatocyte growth factor; Targeted therapy; Receptor tyrosine kinase; Cancer therapeutics

Core tip: Aberrant activation of MET receptor tyrosine kinase signaling is frequently observed in many human cancers. Such activation not only affects cancer development and progression, but it also contributes to resistance against other cancer drugs. The inhibition of MET signaling is an attractive approach for cancer intervention, and pursuit of MET-targeted cancer therapeutics is underway. Even though promising results have been reported from various clinical trials, many challenges remain to be addressed before and even after the arrival of such drugs in the clinic.