Acquired Resistance to EGFR-targeted Therapies in Colorectal Cancer

Mol Oncol. 2014 Sep 12;8(6):1084-94. doi: 10.1016/j.molonc.2014.05.003. Epub 2014 May 14.

Abstract

Cetuximab and panitumumab are anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies used as therapies for metastatic colorectal cancer patients. Intrinsic mechanisms of resistance, such as RAS mutations, can prevent patients from having a response with clinical benefit. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance, which typically occurs within 3-12 months from the start of therapy. Preclinical models and analyses of clinical samples have uncovered some of the alterations that confer a selective advantage to tumor cells when under the pressure of anti-EGFR therapy. Molecular profiling of clinical specimens confirmed that genetic alterations of genes in the EGFR-RAS-RAF-MEK signaling pathway and of receptor tyrosine kinases are mechanisms of acquired resistance to anti-EGFR antibodies. The escape from anti-EGFR blockade appears to converge on the (re)activation of MEK-ERK or AKT as revealed in preclinical studies. Circulating tumor DNA and patient derived xenografts have proven useful tools to monitor patients for resistance to anti-EGFR therapy and test combination therapies to overcome or reverse resistance.

Keywords: Acquired resistance; Anti-EGFR therapy; Cetuximab; Colorectal cancer; MET; Panitumumab; RAS.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Colon / drug effects
  • Colon / metabolism
  • Colon / pathology
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Molecular Targeted Therapy
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rectum / drug effects
  • Rectum / metabolism
  • Rectum / pathology
  • Signal Transduction / drug effects*
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • ras Proteins