Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer

Daniele Oddo, Giulia Siravegna, Annunziata Gloghini, Claudio Vernieri, Benedetta Mussolin, Federica Morano, Giovanni Crisafulli, Rosa Berenato, Giorgio Corti, Chiara Costanza Volpi, Michela Buscarino, Monica Niger, Philip D. Dunne, Giuseppe Rospo, Emanuele Valtorta, Alice Bartolini, Giovanni Fucà, Simona Lamba, Antonia Martinetti, Maria Di BartolomeoFilippo De Braud, Alberto Bardelli, Filippo Pietrantonio, Federica Di Nicolantonio

Research output: Contribution to journalArticle

Abstract

Background:Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF V600E and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.Methods:We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.Results:We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.Conclusions:We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.

Original languageEnglish
Pages (from-to)347-352
Number of pages6
JournalBritish Journal of Cancer
Volume117
Issue number3
DOIs
Publication statusPublished - Jul 25 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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