Mechanisms of tumor resistance to EGFR-targeted therapies

Elizabeth A. Hopper-Borge, Rochelle E. Nasto, Vladimir Ratushny, Louis M. Weiner, Erica A. Golemis, Igor Astsaturov

Research output: Contribution to journalReview articlepeer-review

77 Scopus citations

Abstract

Background : Much effort has been devoted to development of cancer therapies targeting EGFR, based on its role in regulating cell growth. Small-molecule and antibody EGFR inhibitors have clinical roles based on their efficacy in a subset of cancers, generally as components of combination therapies. Many cancers are either initially resistant to EGFR inhibitors or become resistant during treatment, limiting the efficacy of these reagents. Objective/methods: To review cellular resistance mechanisms to EGFR-targeted therapies. Results/conclusions: The best validated of these mechanisms include activation of classic ATP-binding casette (ABC) multidrug transporters; activation or mutation of EGFR; and overexpression or activation of signaling proteins operating in relation to EGFR. We discuss current efforts and potential strategies to override these sources of resistance. We describe emerging systems-biology-based concepts of alternative resistance to EGFR-targeted therapies, and discuss their implications for use of EGFR-targeted and other targeted therapies.

Original languageEnglish
Pages (from-to)339-362
Number of pages24
JournalExpert Opinion on Therapeutic Targets
Volume13
Issue number3
DOIs
StatePublished - Mar 2009

Keywords

  • ATP-Binding Cassette Transporters/metabolism
  • Animals
  • Antineoplastic Agents/pharmacology
  • Drug Delivery Systems
  • Drug Resistance, Neoplasm
  • ErbB Receptors/antagonists & inhibitors
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasms/drug therapy
  • Signal Transduction/drug effects

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