MET in Non-Small-Cell Lung Cancer (NSCLC): Cross 'a Long and Winding Road' Looking for a Target

Abstract

Non-Small-Cell Lung Cancer (NSCLC) can harbour different MET alterations, such as MET overexpression (MET OE), MET gene amplification (MET AMP), or MET gene mutations. Retrospective studies of surgical series of patients with MET-dysregulated NSCLC have shown worse clinical outcomes irrespective of the type of specific MET gene alteration. On the other hand, earlier attempts failed to identify the 'druggable' molecular gene driver until the discovery of MET exon 14 skipping mutations (METex14). METex14 are rare and amount to around 3% of all NSCLCs. Patients with METex14 NSCLC attain modest results when they are treated with immune checkpoint inhibitors (ICIs). New selective MET inhibitors (MET-Is) showed a long-lasting clinical benefit in patients with METex14 NSCLC and modest activity in patients with MET AMP NSCLC. Ongoing clinical trials are investigating new small molecule tyrosine kinase inhibitors, bispecific antibodies, or antibodies drug conjugate (ADCs). This review focuses on the prognostic role of MET, the summary of pivotal clinical trials of selective MET-Is with a focus on resistance mechanisms. The last section is addressed to future developments and challenges.

Keywords: MET; MET amplification; MET exon 14 skipping mutations; MET inhibitors; MET overexpression; NSCLC; immunotherapy; prognosis; resistance mechanism.

Figure 1

HGF/c-MET signaling pathway. Abbreviations: MET = mesenchymal–epithelial transition; HGF = Hepatocyte Growth Factor. RAS = Rat sarcoma virus proteins. BRAF = serine/threonine-protein kinase B-Raf (v-Raf murine sarcoma viral oncogene homolog B); MEK = Mitogen-activated protein kinase kinase; ERK = Extracellular signal-regulated kinases. SOS = Son of sevenless protein (also called guanine nucleotide exchange factor); Shc = Src Homology 2 Domain-Containing (adaptor protein). Grb2 = Growth factor receptor-bound protein 2; Gab1 = GRB2-associated-binding protein 1. STAT3 = signal transducer and activator of transcription 3. PIK3 = Phosphatidylinositol 3-kinases; AKT = Protein-kinase B (also called PKB); NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells; mTOR = mammalian target of rapamycin; RTKs = Receptor Tyrosine kinase pathways; MST1R = Macrophage-stimulating protein receptor 1; ROR1 = Receptor tyrosine kinase-like orphan receptor 1; EGFR = Epidermal growth factor; VEGFR = Vascular endothelial growth factor; HER2 = human epidermal growth factor receptor 2. Created with BioRender.com (accessed on 1 August 2023).

Figure 2

The pathogenesis of MET amplification and MET exon 14 alterations. Description: on the left, the mechanisms by which the MET gene can be amplified (polysomy versus intrachromosomal gene amplification) are depicted; the right shows the physiological mechanism of transcription and translation of the MET gene up to the degradation of the MET receptor and the pathological mechanism of the MET exon 14 skipping leading to the loss of Y1003, which decreased ubiquitination and degradation of the MET receptor. Abbreviations: MET = mesenchymal–epithelial transition; HGF = Hepatocyte Growth Factor; GCN = gene copy number; CEP7 = centromere of chromosome 7; wt = wild type. Created with BioRender.com (accessed on 18 September 2023).

Figure 3

Acquired mechanisms of resistance to MET-Is. Abbreviations: MET TK domain = MET tyrosine kinase domain; MET-Is = MET inhibitors; Crizo = crizotinib; EGF = Epidermal Growth Factor; NRG1 = neuregulin 1; EGFR = EGF receptor; HER3 = human EGFR-3; HER2 = human EGFR2; kRAS = Kirsten rat sarcoma virus gene; BRAF = v-raf murine sarcoma viral oncogene homolog B1 gene; MAPK = mitogen-activated protein kinases pathway; PI3K = Phosphatidylinositol 3-kinase; AKT = Ak strain transforming kinase protein; Mut = mutations; AMP = amplification. References: Recondo G et al. [102]; Dagogo-Jack et al. [104]; Paik K et al. [95].