Local Recurrence in Head and Neck Cancer

• Published in: Clinical cancer research 2002-03, Vol.8 (3), p.885
• Main Authors: Anjali K. Gupta, W. Gillies McKenna, Charles N. Weber, Michael D. Feldman, Jeffrey D. Goldsmith, Rosemarie Mick, Mitchell Machtay, David I. Rosenthal, Vincent J. Bakanauskas, George J. Cerniglia, Eric J. Bernhard, Randal S. Weber, Ruth J. Muschel
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265

Purpose: Locoregional recurrence is the dominant form of treatment failure in head and neck (H&N) cancer. The epidermal growth factor receptor (EGFR) is frequently amplified in this disease (≤80%) and can lead to activation of phosphatidylinositol-3-kinase (PI3K), both directly and indirectly through Ras. We have shown previously that radioresistance could be conferred via the Ras-PI3K pathway. Here we investigate the contribution of EGFR to this pathway and its impact on treatment outcome. Experimental Design: In a series of 38 H&N cancer patients, overexpression of EGFR by immunohistochemical staining was assessed. PI3K signaling was evaluated by staining for phosphorylated Akt (P-Akt), a downstream target of PI3K. Both EGFR and P-Akt were then related to outcome. Radiation survival was determined in the SQ20B cell line, a radioresistant squamous cell line derived from a recurrent laryngeal cancer, after pharmacological blockade of EGFR with Iressa, of Ras by the FTI L744,832, or of PI3K by LY294002. Results: A significant association was found between P-Akt staining and local control in the patient series. Two-year local control was 100% for patients staining 0–1+ for P-Akt as compared with 70.6% for patients staining 2–3+ ( P = 0.04). In our series of 38 H&N cancers, 30 (78.9%) of the specimens were strongly (3+) positive for EGFR, whereas 25 (65.8%) were moderately to strongly (2–3+) positive for P-Akt. Pharmacologically inhibiting EGFR, Ras, and PI3K led to radiosensitization of SQ20B cells. Conclusions: Evaluation of PI3K activation by Akt phosphorylation might be a prognostic marker for response to therapy, and PI3K could be a useful target for therapy. These results also suggest that signaling from EGFR to PI3K can lead to radioresistance.