The Genomic Landscape of Response to EGFR Blockade in Colorectal Cancer

Nature. 2015 Oct 8;526(7572):263-7. doi: 10.1038/nature14969. Epub 2015 Sep 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cetuximab / pharmacology
  • Cetuximab / therapeutic use
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • DNA Copy Number Variations / genetics
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / chemistry
  • ErbB Receptors / genetics
  • Exome / genetics
  • Female
  • Genome, Human / genetics*
  • Genomics*
  • 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

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • KRAS protein, human
  • Panitumumab
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • FGFR1 protein, human
  • Receptor, ErbB-2
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Platelet-Derived Growth Factor alpha
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Proto-Oncogene Proteins p21(ras)
  • Cetuximab