c-MET

OVERVIEW

c-Met, also hepatocyte growth factor receptor (HGFR) is a protein encoded by the MET gene. c-Met has tyrosine kinase activity and is expressed on the surface of epithelial and endothelial cells.¹

The only known ligand for c-Met is hepatocyte growth factor (HGF).¹
HGF binding to c-Met activates multiple intracellular signaling pathways including¹:
- The MAPK/RAS cascade
- The PI3K/AKT cascade
- The STAT pathway
These signaling pathways are responsible for driving proliferation, cell survival, migration and invasiveness.¹
c-Met/HGF are essential for embryonic development and tissue repair.²

IMPLICATIONS IN CANCER

Dysregulated MET signaling in cancer occurs through a variety of genetic or epigenetic mechanisms.^1-3

Germline or somatic mutations, chromosomal rearrangement, or MET amplification
- Increased c-Met protein expression
- Increased MET signaling
Hypoxia-induced overexpression of c-MET
Alteration of other pathways affecting 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, resistance to therapy, and maintenance of cancer stem cells.¹

Notably, alterations in c-Met and/or HGF appear to confer an increased propensity for a more aggressive clinical behavior manifested by invasion, metastasis and resistance to the therapy.¹

Oncogenic Expression

c-Met is overexpressed and has prognostic significance in a variety of solid tumors:

breast cancer (20-30%)⁴
non-small cell lung cancer (37-67%; IHC ≥2+)⁵
gastric cancer (50%)⁶
colorectal cancer (61%)⁷
head and neck cancer (up to 80%)⁸
kidney cancer (~32%)⁹
pancreatic cancer (40-60%)¹⁰

Due to the redundant activation of c-Met-directed pathways, c-Met expression on tumors by itself is not a sufficient predictor for activity of small molecule inhibitors.^11,12

The antitumor activity of c-Met inhibitors is generally limited to a subset of patients with tumors that are driven predominately by MET signaling.
Necessitates selection of patients with MET amplification.

Antibody drug conjugates (ADCs) targeting c-Met represent an attractive therapeutic strategy that does not depend on inhibition of downstream signaling for efficacy but rather on target expression.^11,13

c-Met protein expression is significantly higher in many cancers compared with normal tissues.

Non-Small Cell Lung Cancer

High c-Met expression has been found in NSCLC tumor samples harboring an EGFR mutation.¹²

50% of primary EGFR-TKI-naive NSCLC tumors showed high c-Met expression while only 3% showed c-Met amplification.¹²
A significant correlation was found between c-Met expression and EGFR mutations (p = 0.029).¹²

In advanced-stage NSCLC, MET mutations have a deleterious effect on overall survival (hazard ratio 23.65; p = 0.005) and indicate poor prognosis.¹⁴

Related Research

Antibody-Drug Conjugates

Tumor Intrinsic

Explore AbbVie's Work

Learn More About Investigational Agents Targeting c-Met

Review Clinical Trials

Garajová I, Giovannetti E, Biasco G, Peters GJ. c-Met as a target for personalized therapy. Transl Oncogenomics. 2015;7(Suppl 1):13-31.
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.
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.
Lengyel E, et al. C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer. 2005 Feb 10;113(4):678-82.
Salgia R. MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale. Mol Cancer Ther. 2017;16(4):555-565.
Mo HN, Liu P. Targeting MET in cancer therapy. Chronic Dis Transl Med. 2017; 3(3): 148–153.
Liu Y, et al. Prognostic value of c-Met in colorectal cancer: A meta-analysis. World J Gastroenterol. 2015; 21(12): 3706–3710.
Kim JH, et al. Clinicopathological impacts of high c-Met expression in head and neck squamous cell carcinoma: a meta-analysis and review. Oncotarget. 2017; 8:113120-113128.
Macher-Goeppinger S, et al. MET expression and copy number status in clear-cell renal cell carcinoma: prognostic value and potential predictive marker. Oncotarget. 2017; 8(1): 1046–1057.
Kim JH, et al. Prognostic value of c-Met overexpression in pancreatic adenocarcinoma: a meta-analysis. Oncotarget. 2017; 8(42): 73098–73104.
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.
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.
Strickler JH, et al. First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody–Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors. J Clin Oncol. 2018;36:3298-3306.
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.