The genomic landscape of response to EGFR blockade in colorectal cancer

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

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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.

Original languageEnglish
Pages (from-to)263-267
Number of pages5
JournalNature
Volume526
Issue number7572
DOIs
Publication statusPublished - Oct 8 2015

ASJC Scopus subject areas

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    Bertotti, A., Papp, E., Jones, S., Adleff, V., Anagnostou, V., Lupo, B., Sausen, M., Phallen, J., Hruban, C. A., Tokheim, C., Niknafs, N., Nesselbush, M., Lytle, K., Sassi, F., Cottino, F., Migliardi, G., Zanella, E. R., Ribero, D., Russolillo, N., ... Velculescu, V. E. (2015). The genomic landscape of response to EGFR blockade in colorectal cancer. Nature, 526(7572), 263-267. https://doi.org/10.1038/nature14969