title: Mechanisms of tumor resistance to EGFR-targeted therapies.
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
  To review cellular resistance mechanisms to EGFR-targeted therapies.
  
  
  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.
authors.affiliation: Fox Chase Cancer Center, W462, 333 Cottman Ave., Philadelphia, PA 19111, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hopper-Borge
authors.forename: Rochelle E
authors.initials: RE
authors.lastname: Nasto
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ratushny
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiner
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
authors.forename: Igor
authors.initials: I
authors.lastname: Astsaturov
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D066246:ErbB Receptors