<p>Targeting the MET-Signaling Pathway in Non-Small–Cell Lung Cancer: Evidence to Date</p>

Abstract

The c-MET proto-oncogene (MET) plays an important role in lung oncogenesis, affecting cancer-cell survival, growth and invasiveness. The MET receptor in non-small-cell lung cancer (NSCLC) is a potential therapeutic target. The development of high-output nextgeneration sequencing techniques has enabled better identification of anomalies in the MET pathway, like the MET exon-14 (METex14) mutation. Moreover, analyses of epidermal growth factor-receptor (EGFR) and mechanisms of resistance to tyrosine-kinase inhibitors (TKIs) demonstrated the importance of MET amplification as an escape mechanism in patients with TKI-treated EGFR-mutated NSCLCs. This review summarizes the laboratory findings on MET and its anomalies, trial results on METex14 alterations and MET amplification in non-EGFR mutated NSCLCs, and acquired resistance to TKI in EGFR-mutated NSCLCs. The outcomes of the first trials with anti-MET agents on non-selected NSCLC patients or those selected for MET overexpression were disappointing. Two situations seem the most promising today for the use of anti-MET agents to treat these patients: tumors harboring METex14 and those EGFR-sensitive mutation mutated under TKI-EGFR with a MET-amplification mechanism of resistance or EGFR-resistance mutation.

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

“…More recently, the updated data reported an overall response rate (ORR) of 32% and a median progression-free survival (mPFS) of 7.3 months [21]. Many Phase I-II (e.g., AcSè, METROS) and retrospective analyses confirmed the reported activity and survival results [16,[22][23][24]. In these studies, crizotinib reported similar results in MET-amplified patients.…”

“…The binding of MET to its ligand HGF leads to its homodimerization with subsequent auto-phosphorylation and activation of the intracellular tyrosine kinase domains. The activation of c-MET stimulates many downstream signaling pathways, including mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), mammalian target of rapamycin (mTOR), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways [ 9 , 16 ]. These pathways are involved in cell survival, proliferation, migration, invasion, angiogenesis, and the epithelial-to-mesenchymal transition.…”

“…Gene amplifications are mostly detected by fluorescence in situ hybridization (FISH), but also DNA/RNA sequencing techniques are employed. However, there is no consensus on the definition of MET amplification since different studies have proposed various scores and different cut-offs [ 16 ]. METex 14 mutation can be detected by DNA sequencing or RNA-based sequencing techniques, including next-generation sequencing (NGS), which is the primary detection method, NanoString, and quantitative real-time polymerase chain reaction (qRT-PCR) [ 16 , 18 ].…”

“…In the case of first- and second-generation EGFR-TKI, the exon 20 p.T790M mutation had not been present at disease progression. Capmatinib, cabozantinib, and tepotinib in combination with EGFR-TKIs have already yielded promising antitumor activity in EGFR -mutated, MET -amplified NSCLC patients [ 16 , 18 , 32 ].…”

Anti‐tumor efficacy of human anti‐c‐met CAR‐T cells against papillary renal cell carcinoma in an orthotopic model

“…4,5,7,8 Hepatocyte growth factor receptor, or c-mesenchymalepithelial transition factor (c-met) is a cell surface protein tyrosine kinase. [9][10][11][12] It plays important roles not only in embryogenesis, organ development and differentiation but also in tumor cell migration, proliferation, and invasion in a variety of cancers including breast cancer, lung cancer, and renal cancer. [9][10][11][13][14][15][16][17] Based on these findings, drugs that target c-met, such as TKIs and antibody-drug conjugates, are currently under development, and crizotinib has been approved for non-small-cell lung cancer in some countries.…”