The c-MET proto-oncogene encodes the c-Met receptor tyrosine kinase.

  • The only known ligand for c-Met is hepatocyte growth factor (HGF).1,2
  • HGF binding to c-Met activates multiple downstream signal transduction pathways via autocrine and paracrine loops that trigger normal cell proliferation, survival, and differentiation, including1-4:
    • The MAPK/RAS cascade
    • The AKT/PI3K cascade
    • The STAT3 pathway
    • The NF-ΚB pathway

Implications in cancer

Dysregulated c-Met signaling in cancer occurs through a variety of genetic or epigenetic mechanisms.1,4,5

  • Germline or somatic mutations, chromosomal rearrangement, or c‑Met amplification
    • Increased c-Met protein expression
    • Increased c-Met signaling
  • Hypoxia-induced overexpression of c-Met
  • Alteration of other pathways affecting c-Met transcriptional activation
  • Increased HGF expression

Activation of c-Met directed intracellular signaling pathways is responsible for driving tumor cell proliferation, cell survival, tumor growth, angiogenesis, migration and invasiveness, and maintenance of cancer stem cells.4

Oncogenic Expression

c-Met is overexpressed and has prognostic significance in a variety of solid tumors, including breast cancer (17%), lung cancer (40%), gastric cancer (>95%), colorectal cancer (78%), ovarian cancer (31%), head and neck cancer (>58%), kidney cancer (70%), and pancreatic cancer (>70%).5

Due to the redundant activation of c-Met-directed pathways, many c-Met inhibitors benefit only small subsets of patients with tumors driven by signaling through c-Met.6,7

  • Necessitates selection of patients with c-Met amplification

Non-Small Cell Lung Cancer

c-Met protein overexpression is seen in a majority of NSCLCs.8

  • 50% of primary EGFR-TKI-naive NSCLC tumors showed high c-Met expression while only 3% showed c-Met amplification.7

Very high levels of c-Met overexpression have been found in NSCLC tumor samples harboring an EGFR mutation.7

  • A significant correlation was found between c-Met expression and EGFR mutations (P = .029).

In advanced-stage NSCLC, c-Met mutations have a deleterious effect on overall survival (hazard ratio 23.65; P = .005) and indicate poor prognosis.9

  1. Koeppen H, Yu W, Zha J, et al. Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib ± onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res. 2014;20(17):4488-4498.
  2. Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(1 Suppl):S7-S19.
  3. Reznik TE, Sang Y, Ma Y, et al. Transcription-dependent epidermal growth factor receptor activation by hepatocyte growth factor. Mol Cancer Res. 2008;6(1):139-150.
  4. Garajová I, Giovannetti E, Biasco G, Peters GJ. c-Met as a target for personalized therapy. Transl Oncogenomics. 2015;7(Suppl 1):13-31.
  5. Sierra JR, Tsao MS. c-MET as a potential therapeutic target and biomarker in cancer. Ther Adv Med Oncol. 2011;3(1 Suppl):S21-S35.
  6. Wang J, Anderson MG, Oleksijew A, et al. ABBV-399, a c-Met antibody-drug conjugate that targets both MET-amplified and c-Met-overexpressing tumors, irrespective of MET pathway dependence. Clin Cancer Res. 2017;23(4):992-1000.
  7. Van der Steen N, Deschoolmeester V, Lardon F, et al. cMET in non-small cell lung cancer: pieces of the puzzle. Cancer Res. 2016;76(14 Suppl):Abstract 2242.
  8. Puri N, Salgia R. Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer. J Carcinog. 2008;7:9.
  9. Lim EH, Zhang SL, Li JL, et al. Using whole genome amplification (WGA) of low-volume biopsies to assess the prognostic role of EGFR, KRAS, p53, and CMET mutations in advanced-stage non-small cell lung cancer (NSCLC). J Thorac Oncol. 2009;4(1):12-21.

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