title: Epidermal growth factor receptor inhibitors: coming of age.
abstract: BACKGROUND
  Agents targeting the epidermal growth factor (EGFR)-mediated signaling pathway are used in the treatment of various solid tumors, including lung, breast, pancreatic, colorectal, and head and neck cancers.
  
  
  METHODS
  Clinical evidence supporting the benefits of targeted agents directed against EGFR/HER1 in various solid tumors is discussed, as well as the survival end points used in the pivotal clinical trials, current applications, and future research directions. Agents reviewed include the monoclonal antibodies cetuximab and panitumumab, both of which block ligand binding to the extracellular domain, and the small-molecule tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib that exert their effects at the intracellular portion of the receptor to prevent tyrosine kinase phosphorylation and the activation of signal transduction pathways.
  
  
  RESULTS
  EGFR inhibitors have a mechanism of action distinct from traditional cytotoxic therapies, and combining these agents with chemotherapy produces synergistic anticancer activity without overlapping toxicity profiles. The level of EGFR expression does not correlate with agent response, and many tumors are resistant to treatment. Even if tumors are initially sensitive to these agents, they inevitably acquire resistance through complex, poorly understood molecular mechanisms.
  
  
  CONCLUSIONS
  EGFR-directed therapies have changed the treatment paradigms in metastatic lung, colorectal, and head and neck cancers and improved outcomes. A better understanding of mechanisms of resistance to these agents is crucial for effective drug development. Predictive biomarkers are being developed to deliver personalized therapies.
authors.affiliation: Moffitt Cancer Center, Clinical Research Unit, MCC#3177, Tampa, FL 33647, USA. Amit.Mahipal@Moffitt.org.
authors.forename: Amit
authors.initials: A
authors.lastname: Mahipal
authors.forename: Nishi
authors.initials: N
authors.lastname: Kothari
authors.forename: Shilpa
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D000970:Antineoplastic Agents; C512478:EGFR protein, human; D066246:ErbB Receptors