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Nature. 2015 Oct 8;526(7572):263-7. doi: 10.1038/nature14969. Epub 2015 Sep 30.

The genomic landscape of response to EGFR blockade in colorectal cancer.

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Department of Oncology, University of Turin Medical School, 10060 Candiolo, Turin, Italy.
Translational Cancer Medicine, Surgical Oncology, and Clinical Trials Coordination, Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia IRCCS, 10060 Candiolo, Turin, Italy.
National Institute of Biostructures and Biosystems (INBB), 00136 Rome, Italy.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland 21204, USA.
Department of Surgery, Mauriziano Umberto I Hospital, 10128 Turin, Italy.
Liver Transplantation Center, San Giovanni Battista Hospital, 10126 Turin, Italy.
Department of Surgical Sciences, University of Turin Medical School, 10126 Turin, Italy.
Symphogen A/S, 2750 Ballerup, Denmark.
Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
University of Milan Medical School, 20162 Milan, Italy.
Swim Across America Laboratory, The Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, Baltimore, Maryland 21287, USA.


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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