TY - JOUR
T1 - The genomic landscape of response to EGFR blockade in colorectal cancer
AU - Bertotti, Andrea
AU - Papp, Eniko
AU - Jones, Siân
AU - Adleff, Vilmos
AU - Anagnostou, Valsamo
AU - Lupo, Barbara
AU - Sausen, Mark
AU - Phallen, Jillian
AU - Hruban, Carolyn A.
AU - Tokheim, Collin
AU - Niknafs, Noushin
AU - Nesselbush, Monica
AU - Lytle, Karli
AU - Sassi, Francesco
AU - Cottino, Francesca
AU - Migliardi, Giorgia
AU - Zanella, Eugenia R.
AU - Ribero, Dario
AU - Russolillo, Nadia
AU - Mellano, Alfredo
AU - Muratore, Andrea
AU - Paraluppi, Gianluca
AU - Salizzoni, Mauro
AU - Marsoni, Silvia
AU - Kragh, Michael
AU - Lantto, Johan
AU - Cassingena, Andrea
AU - Li, Qing Kay
AU - Karchin, Rachel
AU - Scharpf, Robert
AU - Sartore-Bianchi, Andrea
AU - Siena, Salvatore
AU - Diaz, Luis A.
AU - Trusolino, Livio
AU - Velculescu, Victor E.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/10/8
Y1 - 2015/10/8
N2 - Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.
AB - Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.
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U2 - 10.1038/nature14969
DO - 10.1038/nature14969
M3 - Article
C2 - 26416732
AN - SCOPUS:84944079826
SN - 0028-0836
VL - 526
SP - 263
EP - 267
JO - Nature
JF - Nature
IS - 7572
ER -