• What is MET?
  • MET in Lung Cancer
  • MET Amplification
  • Clinical Trials

MET

The MET gene (MNNG-HOS transforming geneCooper et al. 1984) located on chromosome 7, encodes a receptor tyrosine kinase (RTK) belonging to the MET/RON family of RTKs. Binding of its ligand, hepatocyte growth factor (HGF; also called scatter factor (SF)), induces a conformational change in the MET receptor that facilitates receptor phosphorylation and activation. Activated MET then phosphorylates its substrates, resulting in activation of multiple downstream pathways within the cell, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1). In the context of malignancy, aberrant signaling through the MET receptor promotes pleiotrophic effects including growth, survival, invasion, migration, angiogenesis and metastasis (Birchmeier et al. 2003; Peruzzi and Bottaro 2006).

The MET receptor and/or its ligand HGF have been reported to be aberrantly activated in many human cancers (see http://www.vai.org/met/). Germline mutations in the tyrosine kinase domain of MET occur in 100% of hereditary papillary renal cell carcinoma, and somatic mutations in MET are found in 10–15% of sporadic papillary renal cell carcinoma (Schmidt et al. 1997). Mutations in MET have been reported at low frequencies in head and neck squamous cell carcinoma (Di Renzo et al. 2000), childhood hepatocellular carcinoma (Park et al. 1999), NSCLC (Kong-Beltran et al. 2006; Ma et al. 2003) and small cell lung cancer (Ma et al. 2003). Amplification of MET has been reported in gastric cancer (Nakajima et al. 1999), esophageal cancer (Miller et al. 2006), colorectal cancer (Umeki, Shiota, and Kawasaki 1999), gliomas (Beroukhim et al. 2007), clear cell ovarian cancer (Yamamoto et al. 2011) and NSCLC (Bean et al. 2007; Cappuzzo et al. 2009; Chen et al. 2009; Engelman et al. 2007; Kubo et al. 2009; Okuda et al. 2008; Onozato et al. 2009).


met.png

Figure 1.
Schematic of the MET signaling pathway. Growth factor binding to MET results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Ben Solomon, M.D.

Suggested Citation: Solomon, B. 2015. MET. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/met/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

MET in Non-Small Cell Lung Cancer (NSCLC)

In non-small cell lung cancer (NSCLC), multiple mechanisms of MET activation have been reported, including gene amplification (Bean et al. 2007; Cappuzzo et al. 2009; Chen et al. 2009; Engelman et al. 2007; Kubo et al. 2009; Okuda et al. 2008; Onozato et al. 2009) and mutation (Kong-Beltran et al. 2006; Ma et al. 2003).

Nonsynonymous MET mutations occurring in the juxtamembrane and semaphorin domains have been described in NSCLC and SCLC (Kong-Beltran et al. 2006; Ma et al. 2003; Ma et al. 2005a). However, some of these were recently identified in corresponding germline DNA (Krishnaswamy et al. 2009). The activity of MET inhibitors in NSCLC or SCLC tumors with non-kinase domain MET mutations is not yet known. By contrast, responses to foretanib (XL880 or GSK136308), an oral inhibitor of MET and other tyrosine kinases including VEGFR2, have been described in patients with papillary renal cell cancer (Eder et al. 2007). 100% of hereditary papillary renal cell carcinomas harbor germline activating mutations in the tyrosine kinase domain of MET (Schmidt et al. 1997).

MET protein expression may also be abnormal in tumors. Overexpression of MET protein in tumor tissue relative to adjacent normal tissues occurs in 25–75% of NSCLC and is associated with poor prognosis (Benedettini et al. 2010; Ichimura et al. 1996; Liu and Tsao 1993; Ma et al. 2005b; Nakamura et al. 2007; Olivero et al. 1996; Siegfried et al. 1998; Xu et al. 2010). In a recent phase II study in which patients with NSCLC were randomized to MetMab (an anti-MET antibody) plus erlotinib vs erlotinib alone, increased expression of MET protein was associated with improved progression free survival and overall survival in patients who received MetMAb and erlotinib (Spigel et al. 2011). Increased MET expression was defined as more than 50% of the tumor having moderate or high MET expression assessed by immunohistochemistry using a specific anti-MET antibody (Ventana CONFIRM anti-CMET clone SP44).

Contributors: Ben Solomon, M.D.

Suggested Citation: Solomon, B. 2014. MET in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/met/ (Updated August 8).

Last Updated: August 8, 2014

MET Amplification in Non-Small Cell Lung Cancer

Properties
Frequency of MET amplification in NSCLC ~2–4% in previously untreated NSCLC
(Bean et al. 2007; Cappuzzo et al. 2009b; Chen et al. 2009; Kubo et al. 2009; Okuda et al. 2008; Onozato et al. 2009)
~5–20% of patients with EGFR-mutated tumors and acquired resistance to EGFR TKIs
(Arcila et al. 2011; Bean et al. 2007; Chen et al. 2009; Engelman et al. 2007; Sequist et al. 2011; Turke et al. 2010)
Implications for Targeted Therapeutics
Response to MET TKIs Confers increased sensitivitya
Response to MET antibodies Unknown at this time
Response to EGFR TKIs Confers decreased sensitivityb
Response to EGFR antibodies Unknown at this time​

Clinically, increased copy number of MET may be detected in tumors by fluorescence in situ hybridization (FISH; Figure 1) or RT-PCR and has been associated with poor prognosis in patients with NSCLC (Cappuzzo et al. 2009a; Go et al. 2010; Okuda et al. 2008). MET amplification is uncommon in previously untreated NSCLC patients and appears to be found in about 2–4% of tumors (Bean et al. 2007; Cappuzzo et al. 2009b; Chen et al. 2009; Kubo et al. 2009; Okuda et al. 2008; Onozato et al. 2009).

a In a case study, a response to crizotinib, an inhibitor of MET and ALK, has been reported in a NSCLC patient with a MET amplified tumor (Ou et al. 2011). In a phase I trial, a 33% response rate was reported in a cohort of 12 MET-amplified NSCLC patients treated with crizotinib (Camidge et al. 2014).

bMET amplification plays a role in acquired resistance to EGFR inhibitors of patients with EGFR-mutated tumors (Bean et al. 2007; Engelman et al. 2007; Turke et al. 2010) and may be seen in 5–20% of patients in this setting (Arcila et al. 2011; Bean et al. 2007; Chen et al. 2009; Engelman et al. 2007; Sequist et al. 2011; Turke et al. 2010).

nsclc-met-amp.jpg

Figure 1.
MET amplification in tumor cells as shown by fluorescence in situ hybridization (FISH). There are increased copies of the red signal (probe binding to MET) compared with the green signal (probe binding to the centromere of chromosome 7).

Contributors: Ben Solomon, M.D.

Suggested Citation: Solomon, B. 2015. MET Amplification in Non-Small Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/met/59/ (Updated March 5).

Last Updated: March 5, 2015

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