Mechanisms of disease: Radiosensitization by epidermal growth factor receptor inhibitors.
The epidermal growth factor receptor (EGFR) inhibitors are among the most intensely studied new molecular therapeutic agents. Although response rates have been somewhat disappointing when EGFR inhibitors are used as single-agent therapy for advanced disease, these inhibitors may be more effective as chemo- and radiosensitizers. The first phase III randomized trial evaluating EGFR inhibitors as radiosensitizers in patients with locally advanced head and neck cancer was strongly positive, indicating significant potential of this class of agents to improve outcome with radiotherapy. However, optimal implementation of EGFR inhibitors as radiosensitizers depends, in part, on a better understanding of the mechanisms of radiosensitization. Preclinical studies provide important observations with regard to potential mechanisms. The phenotypic cellular changes associated with EGFR inhibition are impressively consistent between different model systems, with almost all studies showing that EGFR inhibitors affect proliferation, angiogenesis, and cell survival. Whether EGFR inhibitors influence response to radiation directly, or whether the improved response is a result of additive effects of the two modalities, remains unclear. However, cell-cycle arrest, endothelial cell sensitivity, and apoptotic potential are all important factors in radiation response of epithelial tumors. Furthermore, less-studied effects of EGFR inhibitors on DNA repair suggest that modulation of DNA damage response to cytotoxic injury might result in radio- or chemosensitization. This review will explore potential mechanisms of radiosensitization by EGFR inhibitors.
Sartor
Carolyn I
CI
University of North Carolina/Lineberger Comprehensive Cancer Breast Cancer Program, UNC School of Medicine, Chapel Hill, NC 27599, USA. carolyn_sartor@med.unc.edu
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004260:DNA Repair; D015536:Down-Regulation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; C017867:epidermal growth inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors