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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 (<or=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.

Type

Journal article

Journal

Clin Cancer Res

Publication Date

03/2002

Volume

8

Pages

885 - 892

Keywords

Adult, Aged, Aged, 80 and over, Blotting, Western, Carcinoma, Squamous Cell, Cell Division, Chromones, Dose-Response Relationship, Radiation, Enzyme Inhibitors, ErbB Receptors, Female, Gefitinib, Humans, Immunoenzyme Techniques, Male, Middle Aged, Morpholines, Neoplasm Recurrence, Local, Neoplasm Staging, Oropharyngeal Neoplasms, Phosphatidylinositol 3-Kinases, Phosphorylation, Prognosis, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Quinazolines, Radiation Tolerance, Signal Transduction, ras Proteins