title: Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
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.
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy. alberto.bardelli@unito.it
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.forename: Simona
authors.initials: S
authors.lastname: Corso
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.forename: Sebastijan
authors.initials: S
authors.lastname: Hobor
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valtorta
authors.forename: Giulia
authors.initials: G
authors.lastname: Siravegna
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.forename: Elisa
authors.initials: E
authors.lastname: Scala
authors.forename: Andrea
authors.initials: A
authors.lastname: Cassingena
authors.forename: Davide
authors.initials: D
authors.lastname: Zecchin
authors.forename: Maria
authors.initials: M
authors.lastname: Apicella
authors.forename: Giorgia
authors.initials: G
authors.lastname: Migliardi
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.forename: Calogero
authors.initials: C
authors.lastname: Lauricella
authors.forename: Carlo
authors.initials: C
authors.lastname: Zanon
authors.forename: Timothy
authors.initials: T
authors.lastname: Perera
authors.forename: Silvio
authors.initials: S
authors.lastname: Veronese
authors.forename: Giorgio
authors.initials: G
authors.lastname: Corti
authors.forename: Alessio
authors.initials: A
authors.lastname: Amatu
authors.forename: Marcello
authors.initials: M
authors.lastname: Gambacorta
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Mark
authors.initials: M
authors.lastname: Sausen
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Paolo
authors.initials: P
authors.lastname: Comoglio
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D011905:Genes, ras; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000077544:Panitumumab; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D000077544:Panitumumab; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000068818:Cetuximab