Purpose: Evidence is rapidly mounting that dysregulated epidermal growth factor receptor (EGFR) signaling is one of the underlying mechanisms of more aggressive tumor behavior and increased tumor resistance to cytotoxic agents, including radiotherapy (RT). This has led to extensive preclinical and clinical studies aimed at developing effective treatment strategies that counteract EGFR-mediated signaling. In this article, we review preclinical studies, primarily from our laboratory, addressing the role of EGFR in tumor radioresponse and the use of C225, a human-mouse chimeric anti-EGFR monoclonal antibody, to improve the results of RT.
Methods and materials: Mouse carcinomas were used to study the influence of EGFR on tumor radioresponse. EGFR expression was assessed by Western blot analysis, and cDNA transfection experiments were performed to determine a causal relationship between EGFR and tumor cell radioresistance. A431 human tumor xenografts growing in nude mice were used to test whether blockade of EGFR with C225 anti-EGFR antibody enhances tumor radioresponse.
Results: Our studies showed that high levels of EGFR were associated with decreased tumor radiocurability of murine carcinomas. The causal role of EGFR in mediating cellular resistance to RT was demonstrated by transfecting the EGFR cDNA into the cells with low levels of EGFR. The EGFR-high expression-transfected clones became more resistant to RT. RT activated EGFR and its downstream signaling pathways in radioresistant, but not in radiosensitive, tumors, which can be regarded as an adaptive response to radiation damage. Additional studies investigated whether blockade of EGFR and inhibition of EGFR-mediated downstream signaling can be exploited for therapeutic purposes. The results described here showed that treatment of human tumor xenografts with C225 can markedly enhance the tumor response to RT, as assessed by both tumor growth delay and the tumor cure rate.
Conclusion: The findings from our in vivo preclinical studies suggest that overexpression of EGFR could serve as a predictor of tumor treatment outcome by RT and as a therapeutic target to enhance the efficacy of RT. This therapeutic strategy is currently being explored in patients with head-and-neck cancers.