MET Signaling Pathways, Resistance Mechanisms, and Opportunities for Target Therapies

Abstract

The MET gene, known as MET proto-oncogene receptor tyrosine kinase, was first identified to induce tumor cell migration, invasion, and proliferation/survival through canonical RAS-CDC42-PAK-Rho kinase, RAS-MAPK, PI3K-AKT-mTOR, and β-catenin signaling pathways, and its driver mutations, such as MET gene amplification (METamp) and the exon 14 skipping alterations (METex14), activate cell transformation, cancer progression, and worse patient prognosis, principally in lung cancer through the overactivation of their own oncogenic and MET parallel signaling pathways. Because of this, MET driver alterations have become of interest in lung adenocarcinomas since the FDA approval of target therapies for METamp and METex14 in 2020. However, after using MET target therapies, tumor cells develop adaptative changes, favoring tumor resistance to drugs, the main current challenge to precision medicine. Here, we review a link between the resistance mechanism and MET signaling pathways, which is not only limited to MET. The resistance impacts MET parallel tyrosine kinase receptors and signals shared hubs. Therefore, this information could be relevant in the patient's mutational profile evaluation before the first target therapy prescription and follow-up to reduce the risk of drug resistance. However, to develop a resistance mechanism to a MET inhibitor, patients must have access to the drugs. For instance, none of the FDA approved MET inhibitors are registered as such in Chile and other developing countries. Constant cross-feeding between basic and clinical research will thus be required to meet future challenges imposed by the acquired resistance to targeted therapies.

Keywords: NSCLC; actionable mutations; driver mutations; precision medicine; resistance mutations; target therapies.

Figure 1

Common MET driver mutations impact principally the juxtamembrane and kinase domains (exon 14). Lolliplot of MET protein domains (Sema, PSI, TIG, juxtamembrane, and Pkinase) showing common driver mutations identified in solid tumors from Table 1. Additionally, the protein structure shows the cancer hotspot (yellow circle), OncoKB prediction therapies (blue circles), exons numbered (blue and light blue rectangles), and protein topology. Yellow is the extracellular region, red, the cytoplasmic region, and, gray, the transmembrane region.

Figure 2

Mechanism of resistance to MET target therapies. (A) the on-target resistance mutations. These mutations impacted the Juxtamembrane domain (RED) and the Tyrosine kinase domain (orange). The multi-docking site (brown) without evidence of resistance mutations. (B) Canonical MET signaling pathways acquire resistance mutations such as STAT, PI3K, and KRAS amplification (amp), AKT, mTOR signaling overexpression (arrow up), KRAS mutations, and crosstalk’s mediate PI3Kamp and GSK3b inhibition, Axin downregulation (down arrow) followed by overactivation of b-catenin signaling. (C) The acquired resistance mutations impact the MET parallel receptor tyrosine kinase signaling after using MET-TKI. Therefore, the colors of the target drugs (MET inhibitors) are related to the color of mutations.