Recording and classifying MET receptor mutations in cancers

Abstract

Tyrosine kinase inhibitors (TKI) directed against MET have been recently approved to treat advanced non-small cell lung cancer (NSCLC) harbouring activating MET mutations. This success is the consequence of a long characterization of MET mutations in cancers, which we propose to outline in this review. MET, a receptor tyrosine kinase (RTK), displays in a broad panel of cancers many deregulations liable to promote tumour progression. The first MET mutation was discovered in 1997, in hereditary papillary renal cancer (HPRC), providing the first direct link between MET mutations and cancer development. As in other RTKs, these mutations are located in the kinase domain, leading in most cases to ligand-independent MET activation. In 2014, novel MET mutations were identified in several advanced cancers, including lung cancers. These mutations alter splice sites of exon 14, causing in-frame exon 14 skipping and deletion of a regulatory domain. Because these mutations are not located in the kinase domain, they are original and their mode of action has yet to be fully elucidated. Less than five years after the discovery of such mutations, the efficacy of a MET TKI was evidenced in NSCLC patients displaying MET exon 14 skipping. Yet its use led to a resistance mechanism involving acquisition of novel and already characterized MET mutations. Furthermore, novel somatic MET mutations are constantly being discovered. The challenge is no longer to identify them but to characterize them in order to predict their transforming activity and their sensitivity or resistance to MET TKIs, in order to adapt treatment.

Keywords: cancer; cancer biology; mutation; receptor tyrosine kinase; targeted therapies.

Figure 1.. List of MET mutations found within the functional domains of the receptor.

The extracellular portion of MET consists of the SEMA domain, a PSI domain, and four immunoglobulin-plexin-transcription (IPT) repeats; the intracellular region contains the juxtamembrane domain, the tyrosine kinase domain, and the carboxyterminal docking site. The cancer types in which particular mutations have been identified are noted in parentheses: breast cancer (BC), cancer of unknown primary origin (CUP), colorectal cancer (CRC), gastric cancer (GC), hepatocellular carcinoma (HCC), hereditary papillary renal carcinoma (HPRC), non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), sporadic papillary renal carcinoma (SPRC), malignant pleural mesothelioma (MPM), oropharyngeal squamous cell carcinoma (OSCC), and metastasis (Meta). It is worth noting that the amino acid positions are annotated from MET transcript variant 1 NM_001127500.3 (Tovar and Graveel, 2017; Ma et al., 2005; Ma et al., 2003; Liu et al., 2015; Jardim et al., 2014; Stella et al., 2011; Jagadeeswaran et al., 2006; Moon et al., 2000; Park et al., 1999Bahcall et al., 2016).

Figure 2.. MET mutations leading to exon 14 skipping.

(A) Several mutations affecting the splice junctions flanking exon 14 (encoding the juxtamembrane domain) have been described in non-small cell lung cancer (NSCLC). More than 160 alterations of the exon 14 splicing sites have been described to induce exon skipping and deletion of the MET juxtamembrane domain (Tovar and Graveel, 2017; Ma et al., 2003; Frampton et al., 2015; Lee et al., 2017). (B) Under physiological conditions, MET is also phosphorylated on Tyr1021 in the justamembrane domain, which induces recruitment of Casitas B-lineage lymphoma (CBL), an E3 ubiquitin ligase involved in ubiquitination of the receptor. The ubiquitinated receptor is internalized and degraded, thereby contributing to attenuated signalling. In the absence of its ligand and in response to apoptotic stress, MET is cleaved by caspases to a fragment (p40 MET) able to amplify cell death through permeabilization of the mitochondria. Deletion of the juxtamembrane domain encoded by exon 14 can potentially lead to increased MET stability and tyrosine kinase activity and resistance to cell death. The subsequent increase in proliferation, motility, migration, invasion, and survival promotes tumorigenesis.

Figure 3.. Resistance mutations in the METex14Del variant after treatment with a MET TKI.

(A) Upon treatment of MET exon 14 skipping NSCLC patients with a type I MET TKI (able to bind the active form of MET kinase) or a type II MET TKI (able to bind the inactive form of MET kinase), secondary resistance mutations were identified. Some of them (*) were already known as activating mutations in papillary renal cancer. Note that the amino acid positions are annotated from MET transcript variant NM_000245.3 (Schmidt et al., 1997; Tovar and Graveel, 2017). (B) Secondary activating MET mutations were placed on the 3D structure of the MET kinase domain, along with crizotinib (https://doi.org/10.2210/pdb2WGJ/pdb) or merestinib (https://doi.org/10.2210/pdb4EEV/pdb). MET mutations were inserted into the raw PDB data for MET (Research Collaboratory for Structural Bioinformatics Protein Data Bank DOI: 10.2210/pdb2WGJ/pdb and 10.2210/pdb4EEV/pdb).