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) activation1. Recent studies have identified alterations in KRAS2,3,4 and other genes5,6,7,8,9,10,11,12,13 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.
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Sequence data have been deposited at the European Genome-phenome Archive, which is hosted at the European Bioinformatics Institute, under study accession EGAS00001001305.
We thank S. Angiuoli, D. Riley, L. Kann, M. Shukla, and C. L. McCord for their assistance with next-generation sequencing analyses, and F. Galimi and S. M. Leto for their help with Sanger sequencing analyses and functional studies. This work was supported by the John G. Ballenger Trust, FasterCures Research Acceleration Award, the European Community’s Seventh Framework Programme, the AIRC Italian Association for Cancer Research (Special Program Molecular Clinical Oncology 5×1000, project 9970, and Investigator Grants projects 14205 and 15571), American Association for Cancer Research (AACR) – Fight Colorectal Cancer Career Development Award in memory of Lisa Dubow (project 12-20-16-BERT), the Commonwealth Foundation, Swim Across America, US National Institutes of Health grant CA121113, Fondazione Piemontese per la Ricerca sul Cancro-ONLUS (5×1000 Italian Ministry of Health 2011), Oncologia Ca’ Granda ONLUS, and the SU2C-DCS International Translational Cancer Research Dream Team Grant (SU2C-AACR-DT1415). We acknowledge Merck for a gift of cetuximab. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. A.B. and L.T. are members of the EurOPDX Consortium.
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Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance)
Journal of Clinical Oncology (2019)