Journal Article

The genomic landscape of response to EGFR blockade in colorectal cancer

Adleff, Vilmos, Sassi, Francesco, Muratore, Andrea, Paraluppi, Gianluca, Tokheim, Collin, Cassingena, Andrea, Nesselbush, Monica, Papp, Eniko, Sartore-Bianchi, Andrea, Jones, Siân, Migliardi, Giorgia, Anagnostou, Valsamo, Cottino, Francesca, Scharpf, Robert, Bertotti, Andrea, Sausen, Mark, Lantto, Johan, Salizzoni, Mauro, Trusolino, Livio, Diaz, Luis A., Ribero, Dario, Lytle, Karli, Mellano, Alfredo, Kragh, Michael, Hruban, Carolyn A., Karchin, Rachel, Siena, Salvatore, Li, Qing Kay, Marsoni, Silvia, Velculescu, Victor E., Niknafs, Noushin, Russolillo, Nadia, Phallen, Jillian, Zanella, Eugenia R., Lupo, Barbara

2015

Overview

The effect of somatic genetic changes in colorectal cancer on sensitivity to anti-EGFR antibody therapy is analysed. Genomics of a cancer during targeted therapy Victor Velculescu and colleagues examine the effect of somatic genetic changes in colorectal cancer on sensitivity to a common targeted therapy. Exome sequencing, copy number and targeted analyses of tumour response to anti-EGFR antibody blockade identified mutations in ERBB2 , EGFR , FGFR1 , PDGFRA , and MAP2K1 as potential mechanisms of primary resistance to this therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. In addition to highlighting new mechanisms of responsiveness to anti-EGFR therapies, this work provides new avenues for intervention in the management of colorectal cancer. 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 1 . Recent studies have identified alterations in KRAS 2 , 3 , 4 and other genes 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 13/95 / 45/22 / 45/23 / 631/67 / 631/67/69 / Animals / Antibodies, Monoclonal - pharmacology / Antibodies, Monoclonal - therapeutic use / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Cancer therapies / Care and treatment / Cetuximab - pharmacology / Cetuximab - therapeutic use / Clinical trials / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / DNA Copy Number Variations - genetics / Drug metabolism / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Epidermal growth factor / Exome - genetics / Female / Gene mutations / Genes / Genetic aspects / Genome, Human - genetics / Genomics / Health aspects / Humanities and Social Sciences / Humans / Identification and classification / Insulin Receptor Substrate Proteins - genetics / Kinases / letter / MAP Kinase Kinase 1 - genetics / Mice / Molecular Targeted Therapy / multidisciplinary / Mutation / Mutation - genetics / Proteins / Proto-Oncogene Proteins p21(ras) - genetics / Receptor, Epidermal Growth Factor - antagonists & inhibitors / Receptor, Epidermal Growth Factor - chemistry / Receptor, Epidermal Growth Factor - genetics / Receptor, ErbB-2 - genetics / Receptor, Fibroblast Growth Factor, Type 1 - genetics / Receptor, Platelet-Derived Growth Factor alpha - genetics / Science / Tumors / Xenograft Model Antitumor Assays