MET

MET, also known as proto-oncogene C-Met, is located on the long arm of human chromosome 7 (7q21-31), about 125KB in length, and contains 21 exons (PMID: 2819873). MET is a transmembrane receptor with autonomic phosphorylation activity encoded by MET gene, belonging to the superfamily of receptor Tyrosine kinases (RTKs), which is composed of Sema domain, PSI domain, IPT domain, JM domain, catalytic TK domain and C-terminal domain. It was mainly expressed in epithelial cells (PMID: 22270953). HGF can bind to the Sema domain of MET to induce dimerization and tyrosine phosphorylation of MET, which activates lots of downstream signaling pathways, such as PI3K-AKT, RAS-MAPK, STAT and Wnt/β-catenin, promoting cell proliferation, cell growth, cell migration, invasion of blood vessels and angiogenesis. It plays a key role in normal tissue development and tumor progression (PMID: 1383237, PMID: 7513258, PMID: 22128289, PMID:30513872). Normal expression of MET pathway promotes tissue differentiation and repair, and abnormal regulation promotes tumor cell proliferation and metastasis (PMID: 21102609, PMID: 21102609). Abnormal activation of MET pathway mainly included MET 14 exon jump mutation (about 3%), MET amplification (about 3-7%), MET overexpression (about 25-75%) and rare MET gene fusion (PMID: 28510278). The JM domain encoding the MET 14 exon contains the Y1003 and C-CBL E3 ubiquitin ligase binding site (PMID: 16397241). When the MET 14 exon jump mutation occurs, the binding site of Y1003 and C-CBL is lost, which leads to decreased ubiquitination of the receptor and continuous activation of MET, which is more common in lung cancer (PMID: 28376232). MET amplification, known as copy number amplification, including global chromosome duplication and local regional gene duplication, often accompanied by higher MET protein expression, and is also one of the factors of poor prognosis. MET inhibitors have a significant benefit for patients with high MET amplification (PMID: 17332337, PMID: 16461907). MET activation is caused by many factors, such as other oncodriver genes, hypoxia environment, inflammatory factors, angiogenic factors, and HGF. The most common manifestation of MET activation is protein overexpression caused by transcriptional upregulation, but not as a primary oncodriver, more often as a secondary event generated after activation of other driver genes, thus promoting tumor growth (PMID: 27926778). MET gene has been over expressed in lung cancer, colon cancer, liver cancer and other cancers, and has also been amplified in lung cancer, gastric cancer and other cancer patients that resistant to targeted drug therapy.

MET inhibitors can be divided into three categories: Small molecule tyrosine kinase inhibitors against MET receptors (Crizotinib, Tivantinib, Cabozantinib, Foretinib), monoclonal antibodies against MET receptors (Onartuzumab), and anti-HGF antibodies against their ligands (Ficlatuzumab) , Rilotumumab). Small molecule kinase inhibitors mainly include three types. Type I inhibitors can bind to the active conformation of kinase in ATP pocket. Type II inhibitors that bind to the inactivated conformation of the ATP kinase domain; Type III is a non-ATP competitive allosteric inhibitor (PMID: 19104514). Type Ia inhibitors such as crizotinib interact with residue G1163, Type Ib inhibitors such as tepotinib (MSC2156119), capmatinib (INC280), savolitinib (AZD6094) and APL-101(Apollomics) do not interact with G1163. Type II MET inhibitors include cabozantinib, foretinib (XL-880), merestinib (LY2801653), and glesatinib (MGCD265). In addition to TKIs, there are several MET-oriented therapies currently under development that target the extracellular domain of MET, Includes a mixture of monoclonal antibodies (Sym015), MET X MET Bispecific Antibody (REGN5093), EGFR-MET bispecific antibody (JNJ-61186372), and MET antibo-drug conjugate (ABBV-399, Telisotuzumab vedotin) (PMID: 30404198, PMID: 32532746). Activation and phosphorylation of MET make first-generation EGFR tyrosine kinase inhibitors resistant. Among them, crizotinib is the first MET inhibitor approved by the FDA for the treatment of NSCLC (PMID: 22042947). Capmatinib was also approved by the FDA for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) (PMID: 32557339). A Phase II randomized trial of cabozantinib and erlotinib demonstrated significant efficacy in patients with WT wild-type NSCLC (PMID: 27825638). Earlier reports showed that type I inhibitors crizotinib, capmatinib, tepotinib, and savolitinib showed antitumor activity in the treatment of MET Exon14 mutant NSCLC (PMID: 31932802, PMID: 32557339, PMID: 32027846). Clinical trials on the efficacy of type II TKIs inhibitors cabozantinib and merestinib on nervous system are under way (PMID: 27693535, PMID: 30343896). Crizotinib is an effective option for the treatment of MET-amplified NSCLC, and in the case of resistance to first-generation and second-generation EGFR TKIs, In combination with MET inhibitors such as gefitinib + capmatinib, osimertinib + savolitinib, patients with MET amplification had significant therapeutic effect (PMID: 30156984, PMID: 32027846). Savolitinib or sunitinib are in clinical trials as first-line therapy in renal cell carcinoma (RCC) with MET kinase domain mutation (NCT03091192), and foretinib, a dual inhibitor of MET/VEGFR2, has shown significant efficacy against RCC (PMID: 23213094).