Gastrointestinal malignancies harbor actionable MET exon 14 deletions

Jeeyun Lee, Sai Hong Ignatius Ou, Ji Min Lee, Hee Cheol Kim, Mineui Hong, Sun Young Kim, Jiryeon Jang, Soomin Ahn, So Young Kang, Sujin Lee, Seung Tae Kim, Bogyou Kim, Jaehyun Choi, Kyung Ah Kim, Jiyun Lee, Charny Park, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki KangKeunchil Park, Young Suk Park, Kyoung Mee Kim

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies.

Original languageEnglish
Pages (from-to)28211-28222
Number of pages12
JournalOncotarget
Volume6
Issue number29
DOIs
StatePublished - 2015

Keywords

  • Colorectal carcinoma
  • Crizotinib
  • Gastrointestinal malignancies
  • MET exon 14 skipping
  • MET monoclonal antibodies

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