Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction.
OBJECTIVE
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.


METHODS
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.
Gupta
Anjali K
AK
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6072, USA. gupta@xrt.upenn.edu
McKenna
W Gillies
WG
Weber
Charles N
CN
Feldman
Michael D
MD
Goldsmith
Jeffrey D
JD
Mick
Rosemarie
R
Machtay
Mitchell
M
Rosenthal
David I
DI
Bakanauskas
Vincent J
VJ
Cerniglia
George J
GJ
Bernhard
Eric J
EJ
Weber
Randal S
RS
Muschel
Ruth J
RJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D002455:Cell Division / Q000528:radiation effects; D002867:Chromones / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D009367:Neoplasm Staging; D009959:Oropharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines / Q000494:pharmacology; D011836:Radiation Tolerance; D015398:Signal Transduction; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D002867:Chromones; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D000077156:Gefitinib; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018631:ras Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human