Bringing the Oncology Community Together

MET Inhibitors in Cancer Therapy

Alex A. Adjei, MD, PhD
Published Online: Friday, June 8, 2012
Alex A. Adjei, MD, PhD Corresponding Author:

Alex A. Adjei, MD, PhD

Department of Medicine,
Roswell Park Cancer Institute,
Buffalo, NY;

alex.adjei@roswellpark.org

Abstract

The MET signaling pathway is abnormal in a wide variety of cancers and stimulates cell growth, invasion, and metastasis, as well as promoting resistance to apoptosis. Because of its ubiquitous role in cancer cells, the MET axis has been seen as an attractive target for cancer therapy. Over the last four years, more than 10 anticancer agents targeting different aspects of MET signaling via different mechanisms have been introduced into the clinic. The majority of MET inhibitors are still in late phase I and phase II trials, but at least three compounds, tivantinib, onartuzumab, and cabozantinib, are in phase III trials in lung cancer and medullary thyroid cancer. Ongoing research is aimed at identifying predictive biomarkers that can help identify patients most likely to respond to these compounds. The terminology for this pathway can be confusing. The gene is c-MET, the protein product of the gene is MET.

The MET Signaling Pathway

c-MET was cloned in 1984 and described as a new transforming gene distinct from the then-known RAS family of oncogenes.1 Shortly after c-MET’s initial discovery, its unique high-affinity ligand known as HGF (hepatocyte growth factor, also called scatter factor [SF]), was purified2 and cloned.3 It should be noted that MET is the only known receptor for HGF. The regulatory pathway of MET and HGF governs various cell processes by modulating important signaling cascades in cancer and in normal cells. For example, MET plays a central role in tissue and organ development of embryos, including development of the placenta, liver, and muscle, and the nervous system.4,5 The role of MET in adults is largely restricted to participation in organ regeneration, notably in wound healing, as well as in the pathogenesis of liver, kidney, and heart diseases.6-9

Activation of the MET receptor, usually upon binding of HGF, results in the classic sequence described for receptor tyrosine kinases, including receptor dimerization, phosphorylation of intracellular residues, and initiation of a signal transduction cascade through direct interactions with adaptor proteins, especially GRB2-associated-binding protein 1(GAB1)10, leading to various cellular effects. In addition, the MET pathway interacts with several other cell surface receptors and intracellular pathways, including the HER family (HER1/2/3)11, IGF-1 receptor12, integrins13, and Fas death receptor.14

The Role of the MET Pathway in Cancer

In experimental cancer models, increased signaling through the MET pathway results in acquisition or reinforcement of all elements of the malignant phenotype. These include tumor cell proliferation, motility, invasiveness, migration, and survival. In addition, endothelial cell proliferation and motility occur, resulting in tumor angiogenesis.15 It should also be noted that MET is expressed not only in tumor cells and endothelial cells, but also in osteoblasts (bone-forming cells) and osteoclasts (bone-removing cells). HGF binds to MET on all of these cell types, giving the MET pathway an important role in multiple autocrine and paracrine loops. Activation of MET in tumor cells appears to be important in the establishment of metastatic bone lesions. At the same time, activation of the MET pathway in osteoblasts and osteoclasts may lead to pathological features of bone metastases, including abnormal bone growth (ie, blastic lesions) or destruction (ie, lytic lesions). Thus, targeting the MET pathway may be a viable strategy in preventing the establishment and progression of metastatic bone lesions.

The MET pathway is abnormally regulated in a wide range of human cancers, including the most common epithelial cancers such as breast, colorectal, lung, pancreatic, hepatic, and ovarian cancers.16 Aberrant MET signaling results from several molecular mechanisms, including germline or somatic c-MET gene mutation, c-MET chromosomal rearrangement, c-MET amplification, c-MET transcriptional upregulation, or ligand-dependent autocrine or paracrine changes. These mechanisms are described briefly following.

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