Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer

Cancer Discov. 2013 Jun;3(6):658-73. doi: 10.1158/2159-8290.CD-12-0558. Epub 2013 Jun 2.

Abstract

EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology*
  • Cetuximab
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • Genes, ras
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Panitumumab
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Proto-Oncogene Proteins c-met / pharmacology*
  • Random Allocation
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Panitumumab
  • ErbB Receptors
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Cetuximab