Growing evidence suggests that epidermal growth factor family receptors (HERs) play a significant role in radiation response. EGFR expression levels and activation by ligand correlate with radioresistance, and exogenous HER2 expression alters radiation response. Preclinical studies of anti-EGFR anti-HER2 antibodies, and kinase inhibitors that inhibit EGFR, both EGFR and HER2, or all 4 family members show potential for clinical radiosensitization. Early-phase clinical trials of the anti-EGFR antibody, C225, prove the combination of C225 and radiotherapy to be well tolerated and promising. A phase 3 randomized trial in head and neck cancer is underway, and clinical investigation of other HER inhibitors is in progress. The mechanisms(s) of radiation response modulation by HERs appear complex and diverse. Signal transduction initiated by receptor activation promotes survival and proliferation after ionizing radiation, and HER inhibitors affect cellular responses to ionizing radiation (IR) in diverse ways, including inducing apoptosis, cell cycle arrest, and impeding DNA repair. HER signaling and inhibition also affect tumor-stroma interactions, particularly angiogenesis and endothelial survival after IR. Further investigation of the radiation response modulation by EGFR family members and their inhibitors will lead to optimization of this promising therapeutic approach.
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