Targeting MET Dysregulation in Cancer

Abstract

Aberrant MET signaling can drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET gene amplification, mutation, rearrangement, and overexpression. Improvements in biomarker discovery and testing have more recently enabled the selection of patients with MET-dependent cancers for treatment with potent, specific, and novel MET-targeting therapies. We review the known oncologic processes that activate MET, discuss therapeutic strategies for MET-dependent malignancies, and highlight emerging challenges in acquired drug resistance in these cancers. SIGNIFICANCE: Increasing evidence supports the use of MET-targeting therapies in biomarker-selected cancers that harbor molecular alterations in MET. Diverse mechanisms of resistance to MET inhibitors will require the development of novel strategies to delay and overcome drug resistance.

Figure 1.. Mechanisms of MET oncogenic activation.

(A) MET activation is initiated after ligand binding of the hepatocyte growth factor (HGF) to the SEMA domain to the extracellular portion of the MET receptor, inducing receptor dimerization and phosphorylation of the intracellular domain leading to downstream signaling of several pathways. The E3 ubiquitin ligase CBL binds to reside Y1003 in the juxtamembrane domain (encoded in part by exon 14), resulting in receptor ubiquitination and degradation. MET exon 14 alterations including mutations or deletions in splicing regulatory sites, leading to exon skipping, deletion of a portion of the juxtamembrane domain, impaired CBL binding, decreased MET turnover, and ongoing oncogenic downstream pathway signaling. (B) Point mutations in the tyrosine kinase domain result in ligand-independent MET activation through autophosphorylation of the tyrosine kinase domain, conveying sustained oncogenic downstream pathway signaling. (C) Focal MET amplification leads to higher levels of MET transcription and MET expression. MET amplification (high MET/CEP7 ratio) differs from chromosome 7 polysomy or copy number gain in which the entire chromosome is duplicated (low MET/CEP7 ratio). Focal MET amplification and, consequently high MET expression, leads to enhanced ligand-independent oncogenic signaling by receptor auto-dimerization or oligomerization and auto-phosphorylation. (D) Gene rearrangements involving the MET tyrosine kinase domain result in fusion proteins that typically self-dimerize in a ligand-independent manner, leading to phosphorylation of the tyrosine kinase domain.

Figure 2.. Mechanisms of resistance to MET tyrosine kinase inhibitors in MET exon 14 mutant lung cancer.

Crystal modelling of the MET kinase domain and binding of MET tyrosine kinase inhibitors (green). The figure displays the position of frequently mutated residues within the MET kinase domain including G1163 (red), D1228 (purple), Y1230 (blue), L1195 (yellow), and F1200 (orange) that confer acquired resistance to MET TKIs. Panel A displays interaction of the type Ia MET TKI crizotinib (PDB Ref: 2WGJ) with commonly mutated residues that confer resistance to crizotinib like G1163R, D1228X and Y1230X mutations. Panel B shows the interaction of the type Ib MET inhibitor savolitinib analog (PDB Ref: 3ZC5) with resistance mutations including D1228X and Y1230X, but the interaction with the kinase domain is not predicted to be affected by the G1163R solvent front mutation. In panel C, the type II MET TKI merestinib (PDB Ref: 4EEV) is simulated bound to the kinase domain and displays the interaction of type II MET inhibitors with key residues that can cause resistance to these compounds like L1195F/V and F1200L.