Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer

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 GambacortaLuis A. Diaz, Mark Sausen, Victor E. Velculescu, Paolo Comoglio, Livio Trusolino, Federica Di Nicolantonio, Silvia Giordano, Salvatore Siena

Research output: Contribution to journalArticle

378 Citations (Scopus)

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. SIGNIFICANCE: Amplification of the MET proto-oncogene is responsible for de novo and acquired resistance to anti-EGFR therapy in a subset of colorectal cancers. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies.

Original languageEnglish
Pages (from-to)658-673
Number of pages16
JournalCancer Discovery
Volume3
Issue number6
DOIs
Publication statusPublished - 2013

Fingerprint

Epidermal Growth Factor Receptor
Colorectal Neoplasms
Proto-Oncogenes
Therapeutics
Mutation
Heterografts
Neoplasms
Phosphotransferases
Monoclonal Antibodies
Recurrence
DNA

ASJC Scopus subject areas

  • Oncology

Cite this

Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. / Bardelli, Alberto; Corso, Simona; Bertotti, Andrea; Hobor, Sebastijan; Valtorta, Emanuele; Siravegna, Giulia; Sartore-Bianchi, Andrea; Scala, Elisa; Cassingena, Andrea; Zecchin, Davide; Apicella, Maria; Migliardi, Giorgia; Galimi, Francesco; Lauricella, Calogero; Zanon, Carlo; Perera, Timothy; Veronese, Silvio; Corti, Giorgio; Amatu, Alessio; Gambacorta, Marcello; Diaz, Luis A.; Sausen, Mark; Velculescu, Victor E.; Comoglio, Paolo; Trusolino, Livio; Di Nicolantonio, Federica; Giordano, Silvia; Siena, Salvatore.

In: Cancer Discovery, Vol. 3, No. 6, 2013, p. 658-673.

Research output: Contribution to journalArticle

Bardelli, A, Corso, S, Bertotti, A, Hobor, S, Valtorta, E, Siravegna, G, Sartore-Bianchi, A, Scala, E, Cassingena, A, Zecchin, D, Apicella, M, Migliardi, G, Galimi, F, Lauricella, C, Zanon, C, Perera, T, Veronese, S, Corti, G, Amatu, A, Gambacorta, M, Diaz, LA, Sausen, M, Velculescu, VE, Comoglio, P, Trusolino, L, Di Nicolantonio, F, Giordano, S & Siena, S 2013, 'Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer', Cancer Discovery, vol. 3, no. 6, pp. 658-673. https://doi.org/10.1158/2159-8290.CD-12-0558
Bardelli, Alberto ; Corso, Simona ; Bertotti, Andrea ; Hobor, Sebastijan ; Valtorta, Emanuele ; Siravegna, Giulia ; Sartore-Bianchi, Andrea ; Scala, Elisa ; Cassingena, Andrea ; Zecchin, Davide ; Apicella, Maria ; Migliardi, Giorgia ; Galimi, Francesco ; Lauricella, Calogero ; Zanon, Carlo ; Perera, Timothy ; Veronese, Silvio ; Corti, Giorgio ; Amatu, Alessio ; Gambacorta, Marcello ; Diaz, Luis A. ; Sausen, Mark ; Velculescu, Victor E. ; Comoglio, Paolo ; Trusolino, Livio ; Di Nicolantonio, Federica ; Giordano, Silvia ; Siena, Salvatore. / Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. In: Cancer Discovery. 2013 ; Vol. 3, No. 6. pp. 658-673.
@article{8144c760aea946b1affcb723602789a6,
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. SIGNIFICANCE: Amplification of the MET proto-oncogene is responsible for de novo and acquired resistance to anti-EGFR therapy in a subset of colorectal cancers. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies.",
author = "Alberto Bardelli and Simona Corso and Andrea Bertotti and Sebastijan Hobor and Emanuele Valtorta and Giulia Siravegna and Andrea Sartore-Bianchi and Elisa Scala and Andrea Cassingena and Davide Zecchin and Maria Apicella and Giorgia Migliardi and Francesco Galimi and Calogero Lauricella and Carlo Zanon and Timothy Perera and Silvio Veronese and Giorgio Corti and Alessio Amatu and Marcello Gambacorta and Diaz, {Luis A.} and Mark Sausen and Velculescu, {Victor E.} and Paolo Comoglio and Livio Trusolino and {Di Nicolantonio}, Federica and Silvia Giordano and Salvatore Siena",
year = "2013",
doi = "10.1158/2159-8290.CD-12-0558",
language = "English",
volume = "3",
pages = "658--673",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer

AU - Bardelli, Alberto

AU - Corso, Simona

AU - Bertotti, Andrea

AU - Hobor, Sebastijan

AU - Valtorta, Emanuele

AU - Siravegna, Giulia

AU - Sartore-Bianchi, Andrea

AU - Scala, Elisa

AU - Cassingena, Andrea

AU - Zecchin, Davide

AU - Apicella, Maria

AU - Migliardi, Giorgia

AU - Galimi, Francesco

AU - Lauricella, Calogero

AU - Zanon, Carlo

AU - Perera, Timothy

AU - Veronese, Silvio

AU - Corti, Giorgio

AU - Amatu, Alessio

AU - Gambacorta, Marcello

AU - Diaz, Luis A.

AU - Sausen, Mark

AU - Velculescu, Victor E.

AU - Comoglio, Paolo

AU - Trusolino, Livio

AU - Di Nicolantonio, Federica

AU - Giordano, Silvia

AU - Siena, Salvatore

PY - 2013

Y1 - 2013

N2 - 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. SIGNIFICANCE: Amplification of the MET proto-oncogene is responsible for de novo and acquired resistance to anti-EGFR therapy in a subset of colorectal cancers. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies.

AB - 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. SIGNIFICANCE: Amplification of the MET proto-oncogene is responsible for de novo and acquired resistance to anti-EGFR therapy in a subset of colorectal cancers. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies.

UR - http://www.scopus.com/inward/record.url?scp=84878862323&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878862323&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-12-0558

DO - 10.1158/2159-8290.CD-12-0558

M3 - Article

C2 - 23729478

AN - SCOPUS:84878862323

VL - 3

SP - 658

EP - 673

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 6

ER -