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The genomic landscape of response to EGFR blockade in colorectal cancer.
- Source :
-
Nature [Nature] 2015 Oct 08; Vol. 526 (7572), pp. 263-7. Date of Electronic Publication: 2015 Sep 30. - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Antibodies, Monoclonal pharmacology
Antibodies, Monoclonal therapeutic use
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Cetuximab pharmacology
Cetuximab therapeutic use
Colorectal Neoplasms metabolism
DNA Copy Number Variations genetics
ErbB Receptors chemistry
ErbB Receptors genetics
Exome genetics
Female
Humans
Insulin Receptor Substrate Proteins genetics
MAP Kinase Kinase 1 genetics
Mice
Molecular Targeted Therapy
Mutation genetics
Panitumumab
Proto-Oncogene Proteins p21(ras) genetics
Receptor, ErbB-2 genetics
Receptor, Fibroblast Growth Factor, Type 1 genetics
Receptor, Platelet-Derived Growth Factor alpha genetics
Xenograft Model Antitumor Assays
Colorectal Neoplasms drug therapy
Colorectal Neoplasms genetics
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
ErbB Receptors antagonists & inhibitors
Genome, Human genetics
Genomics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 526
- Issue :
- 7572
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 26416732
- Full Text :
- https://doi.org/10.1038/nature14969