MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition in BRAF- Mutated Colorectal Cancer

Filippo Pietrantonio, Daniele Oddo, Annunziata Gloghini, Emanuele Valtorta, Rosa Berenato, Ludovic Barault, Marta Caporale, Adele Busico, Federica Morano, Ambra Vittoria Gualeni, Alessandra Alessi, Giulia Siravegna, Federica Perrone, Maria Di Bartolomeo, Alberto Bardelli, Filippo De Braud, Federica Di Nicolantonio

Research output: Contribution to journalArticle

Abstract

A patient with metastatic BRAF -mutated colorectal cancer initially responded to
combined EGFR and BRAF inhibition with panitumumab plus vemurafenib. Preexisting cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment, leading to the emergence of MET amplifi cation in the rebiopsy taken at progression. In BRAF -mutated colorectal cancer cells, ectopic expression of MET conferred
resistance to panitumumab and vemurafenib, which was overcome by combining BRAF and MET inhibition.
Based on tumor genotyping and functional in vitro data, the patient was treated with the dual ALK–MET inhibitor crizotinib plus vemurafenib, thus switching to dual MET and BRAF blockade, with rapid and marked effectiveness of such strategy. Although acquired resistance is a major limitation to
the clinical effi cacy of anticancer agents, the identifi cation of molecular targets emerging during the first treatment may afford the opportunity to design the next line of targeted therapies, maximizing patient benefit.
SIGNIFICANCE: MET amplifi cation is here identifi ed—clinically and preclinically—as a new mechanism of resistance to EGFR and BRAF dual/triple block combinations in BRAF -mutated colorectal cancer.
Switching from EGFR to MET inhibition, while maintaining BRAF inhibition, resulted in clinical benefit after the occurrence of MET-driven acquired resistance.
Original languageEnglish
JournalCancer Discovery
Publication statusPublished - 2016

Fingerprint Dive into the research topics of 'MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition in BRAF- Mutated Colorectal Cancer'. Together they form a unique fingerprint.

  • Cite this