title: The genomic landscape of response to EGFR blockade in colorectal cancer.
abstract: 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.
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Eniko
authors.initials: E
authors.lastname: Papp
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Vilmos
authors.initials: V
authors.lastname: Adleff
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Valsamo
authors.initials: V
authors.lastname: Anagnostou
authors.affiliation: 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.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lupo
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sausen
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Phallen
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Hruban
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland 21204, USA.
authors.forename: Collin
authors.initials: C
authors.lastname: Tokheim
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland 21204, USA.
authors.forename: Noushin
authors.initials: N
authors.lastname: Niknafs
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Nesselbush
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Karli
authors.initials: K
authors.lastname: Lytle
authors.affiliation: Translational Cancer Medicine, Surgical Oncology, and Clinical Trials Coordination, Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia IRCCS, 10060 Candiolo, Turin, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sassi
authors.affiliation: Translational Cancer Medicine, Surgical Oncology, and Clinical Trials Coordination, Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia IRCCS, 10060 Candiolo, Turin, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cottino
authors.affiliation: 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.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Migliardi
authors.affiliation: 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.
authors.forename: Eugenia R
authors.initials: ER
authors.lastname: Zanella
authors.affiliation: Department of Surgery, Mauriziano Umberto I Hospital, 10128 Turin, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Ribero
authors.affiliation: Department of Surgery, Mauriziano Umberto I Hospital, 10128 Turin, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Russolillo
authors.affiliation: Translational Cancer Medicine, Surgical Oncology, and Clinical Trials Coordination, Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia IRCCS, 10060 Candiolo, Turin, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Mellano
authors.affiliation: Translational Cancer Medicine, Surgical Oncology, and Clinical Trials Coordination, Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia IRCCS, 10060 Candiolo, Turin, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Muratore
authors.affiliation: Liver Transplantation Center, San Giovanni Battista Hospital, 10126 Turin, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Paraluppi
authors.affiliation: Liver Transplantation Center, San Giovanni Battista Hospital, 10126 Turin, Italy.|Department of Surgical Sciences, University of Turin Medical School, 10126 Turin, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Salizzoni
authors.affiliation: Translational Cancer Medicine, Surgical Oncology, and Clinical Trials Coordination, Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia IRCCS, 10060 Candiolo, Turin, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.affiliation: Symphogen A/S, 2750 Ballerup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Kragh
authors.affiliation: Symphogen A/S, 2750 Ballerup, Denmark.
authors.forename: Johan
authors.initials: J
authors.lastname: Lantto
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cassingena
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Qing Kay
authors.initials: QK
authors.lastname: Li
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.|Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland 21204, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Scharpf
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.|University of Milan Medical School, 20162 Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.|Swim Across America Laboratory, The Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, Baltimore, Maryland 21287, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.affiliation: 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.
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000068818:Cetuximab / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D055504:Insulin Receptor Substrate Proteins; D048369:MAP Kinase Kinase 1; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; C526297:IRS2 protein, human; C117307:KRAS protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C496348:FGFR1 protein, human; C482125:MAP2K1 protein, human