Amplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer

Overview

Journal Cancer Discov

Specialty Oncology

Date 2013 Jun 5

PMID 23729478

Citations 340

Authors

Alberto Bardelli

Simona Corso

Andrea Bertotti

Sebastijan Hobor

Emanuele Valtorta

Giulia Siravegna

Andrea Sartore-Bianchi

Elisa Scala

Andrea Cassingena

Davide Zecchin

Maria Apicella

Giorgia Migliardi

Francesco Galimi

Calogero Lauricella

Carlo Zanon

Timothy Perera

Silvio Veronese

Giorgio Corti

Alessio Amatu

Marcello Gambacorta

Luis A Diaz Jr

Mark Sausen

Victor E Velculescu

Paolo Comoglio

Livio Trusolino

Federica Di Nicolantonio

Silvia Giordano

Salvatore Siena

Affiliations

Soon will be listed here.

Abstract

EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification.

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