MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition in BRAF-Mutated Colorectal Cancer.
A patient with metastatic BRAF-mutated colorectal cancer initially responded to combined EGFR and BRAF inhibition with panitumumab plus vemurafenib. Pre-existing cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment, leading to the emergence of MET amplification 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 efficacy of anticancer agents, the identification of molecular targets emerging during the first treatment may afford the opportunity to design the next line of targeted therapies, maximizing patient benefit.



MET amplification is here identified-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. Cancer Discov; 6(9); 963-71. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. filippo.pietrantonio@istitutotumori.mi.it.
Filippo
F
Pietrantonio
Department of Oncology, University of Torino, Candiolo (TO), Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo (TO), Italy.
Daniele
D
Oddo
Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Annunziata
A
Gloghini
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Emanuele
E
Valtorta
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Rosa
R
Berenato
Candiolo Cancer Institute-FPO, IRCCS, Candiolo (TO), Italy.
Ludovic
L
Barault
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Marta
M
Caporale
Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Adele
A
Busico
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Federica
F
Morano
Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Ambra Vittoria
AV
Gualeni
Nuclear Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Alessandra
A
Alessi
Department of Oncology, University of Torino, Candiolo (TO), Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo (TO), Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy.
Giulia
G
Siravegna
Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Federica
F
Perrone
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Maria
M
Di Bartolomeo
Department of Oncology, University of Torino, Candiolo (TO), Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo (TO), Italy.
Alberto
A
Bardelli
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Department of Oncology, Università degli Studi di Milano, Milan, Italy.
Filippo
F
de Braud
Department of Oncology, University of Torino, Candiolo (TO), Italy. Candiolo Cancer Institute-FPO, IRCCS, Candiolo (TO), Italy.
Federica
F
Di Nicolantonio
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D057915:Drug Substitution; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005784:Gene Amplification; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D009154:Mutation; D000077544:Panitumumab; D000072078:Positron Emission Tomography Computed Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology; D014057:Tomography, X-Ray Computed; D000077484:Vemurafenib
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D000077544:Panitumumab; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D048493:Proto-Oncogene Proteins B-raf