Resistance to epidermal growth factor receptor-targeted therapy.
The epidermal growth factor receptor (EGFR) has been a major target of molecular anticancer therapy. Two approaches have been developed, involving monoclonal antibodies and receptor tyrosine kinase inhibitors, and both have demonstrated benefit in clinical trials. However, evidence of resistance to these drugs has been described. Cellular levels of EGFR do not always correlate with response to the EGFR tyrosine kinase inhibitors, indicating acquired resistance to these drugs. Since EGFR antagonists interfere with the activation of several intracellular pathways that control cell proliferation, survival, apoptosis, angiogenesis, invasion and metastasis, acquired resistance can occur as a result of several different molecular mechanisms: autocrine/paracrine production of ligand, receptor mutation, constitutive activation of the downstream pathway and activation of alternative pathways. We will describe here potential mechanisms that can cause resistance to EGFR-targeted drugs. Combinations of EGFR antagonists with inhibitors targeting different signaling mechanism(s) - such as insulin-like growth factor receptor and vascular endothelial growth factor receptor - that share the same downstream mediator (e.g., phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase), may circumvent or delay the development of resistance to EGFR antagonists resulting in enhanced antitumor activities.
Morgillo
Floriana
F
Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Lee
Ho-Young
HY
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors