MET
The MET gene (MNNG-HOS transforming gene; Cooper 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).

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.mycancergenome.org/content/disease/lung-cancer/met/?tab=0 (Updated December 7).
Last Updated: December 7, 2015
MET in Non-Small Cell Lung Cancer (NSCLC)
Contributors: Ben Solomon, M.D.
Suggested Citation: Solomon, B. 2014. MET in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.mycancergenome.org/content/disease/lung-cancer/met/ (Updated August 8).
Last Updated: August 8, 2014
MET Exon 14 Skipping Mutations in Lung Cancer
MET alterations that result in exon 14 skipping are found in lung cancer in both the presence and absence of MET amplification (Awad et al. 2016; Frampton et al. 2015; Jenkins et al. 2015; Kollmannsberger et al. 2015; Liu et al. 2015; Onozato et al. 2009; Paik et al. 2015; Seo et al. 2012; TGCA 2014). Over 100 mutations in MET-mutated cancers resulting in exon 14 skipping have been described (Frampton et al. 2015). Exon 14 skipping results in the deletion of the juxtamembrane domain of MET, which leads to enhanced signaling through the MET receptor pathway (Kong-Beltran et al. 2006). This alteration is tumorigenic in xenograft models (Kong-Beltran et al. 2006).
a Both preclinical and case report evidence suggest that tumors harboring MET with exon 14 alterations and/or MET amplifications have increased sensitivity to MET inhibitors.
Reference |
Study Type |
Diagnosis |
Reported Alterations |
Line of Metastatic Therapy |
Therapy |
Best Response |
Duration of Response |
Jenkins et al. 2015 |
Case report |
Lung adenocarcinoma |
MET c.2887-18_2887-7del12 exon 14 splicing variant
CDKN2A/B-loss
CDK4 amplification
MDM2 amplification
|
Second |
Crizotinib |
Partial reponse |
13 weeks (progression occured after therapy discontinuation |
Paik et al. 2015 |
Case reports |
Lung adenocarcinoma (poorly differentiated) |
MET c. 3028G>C exon 14 splicing variant
MET amplification
RB1 intragenic deletion
DICER1 Q1776*
EPHA5 R853Q
KLF4 M1I
MLL I1929M
MTOR D537N
TERT G225E
FUBP1 amplification
GSK3B amplification
SDHA amplification
TERT amplification
KDM5A amplification
RAD52 amplification
MDM2 amplification
BCL2L1 amplification
NKX3-1 deletion
ETV6 deletion
|
Third |
Cabozantinib |
Stable disease |
5.1 months (ongoing) |
Lung adenocarcinoma |
MET c.3024_3028+7delAGAAGGTATATT exon 14 splicing variant
TP53 exon 8 splice variant
FAT1 R782fs
FBXW7 G539V
MLL E1678K
NF1 E572fs
NTKR2 I191T
YES1 amplification
|
Third |
Crizotinib |
Partial reponse |
3.6 months |
Lung adenocarcinoma |
MET c.3001_3021delGTAGACTACCGAGCTACTTTT
MET amplification
TP53 R248P
RB1 intragenic deletion
BRCA1 E648Q
MYC E137D
NF1 exon 56 splice variant
NDS1 E1902K
PDGFRB R397W
TERT gain
MYC amplification
NKX2-1 amplification
|
Third |
Crizotinib |
Partial reponse |
4.6 months (ongoing) |
Lung adenocarcinoma |
MET c.3028G>T exon 14 splicing variant
CDK4 amplification
MDM2 amplification
|
Third |
Crizotinib |
Partial reponse |
3.1 months (ongoing) |
Liu et al. 2015 |
Case report |
Pulmonary sarcomatoid carcinoma |
MET c.2888delA exon 14 splicing variant
MET amplification
|
Third |
Crizotinib |
Partial reponse |
NR |
Lee et al. 2015 |
Case report |
Sarcomatoid non-small cell lung carcinoma |
MET c.2888-5_2890TTAAGATC>A exon 14 splicing variant
MET c.3028+2T>G
|
Second |
Crizotinib |
Partial reponse |
5 months |
Frampton et al. 2015 |
Case reports |
Large cell lung carcinoma |
MET c.3028G>C exon 14 splicing variant
MET amplification
TP53 p.N30fs
|
First |
Capmatinib |
Partial reponse |
5 months |
Lung squamous cell carcinoma |
MET c.3028+1G>T exon 14 splicing variant
MET amplification
|
Third |
Capmatinib |
Partial reponse |
13 months |
Kollmannsberger et al. 2015 |
Case reports |
Lung adenocarcinoma |
MET c.2888-6_29del exon 14 splicing variant
|
Third |
MGCD265 |
Partial reponse |
5 cycles (ongoing) |
Lung adenocarcinoma |
MET c.3028+1G>T exon 14 splicing variant |
First |
MGCD265 |
Partial reponse |
6 cycles (ongoing) |
Schrock et al. 2016 |
Case reports |
Lung adenocarcinoma |
MET c.3028+1_3028+1delG exon 14 splicing variant
MET amplification
CDK4 amplification
|
NR |
Crizotinib |
Partial reponse |
24 months |
Lung adenocarcinoma |
MET D1010Y
|
NR |
Crizotinib |
Partial reponse |
7 months (ongoing) |
Lung adenocarcinoma |
MET c.3028+1delG exon 14 splicing variant
MET amplification
MDM2 amplification
|
NR |
Crizotinib |
Complete reponse |
7 months (ongoing) |
Lung adenocarcinoma |
MET D1010H
|
NR |
Crizotinib |
Stable Disease |
4 months (ongoing) |
Lung adenocarcinoma |
MET c.2888-16_2888-3del14 exon 14 splicing variant
MET amplification
MDM2 amplification
|
NR |
Crizotinib |
Partial reponse |
10 months (ongoing) |
Lung squamous cell carcinoma |
MET c.2888-11_2904del28 exon 14 splicing variant
|
NR |
Crizotinib |
Partial reponse |
NR |
Lung adenocarcinoma |
MET c.2888-16_2888-13delTTCT exon 14 splicing variant
|
NR |
Crizotinib |
Complete reponse |
3 months (ongoing) |
Lung adenocarcinoma |
MET c.3028+1G>A exon 14 splicing variant
|
NR |
Crizotinib |
Complete reponse |
Unresectable to resectable and NED after resection |
Awad et al. 2016 |
Case report |
Lung adenocarcinoma (poorly differentiated) |
MET c.3028G>A exon 14 splicing variant
MET amplification
|
Second |
Crizotinib |
Partial reponse |
8 months (ongoing) |
Notes: NR = Not reported; NED = No evidence of disease
Contributors: Christine M. Lovly, M.D., Ph.D., Paul K. Paik, M.D.
Suggested Citation: Lovly, C., P. Paik. 2017. MET Exon 14 Skipping Mutations in Lung Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/lung-cancer/met/343/ (Updated June 15).
Last Updated: June 15, 2017
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