The Ras radiation resistance pathway

The critical pathways determining the resistance of tumor cells to ionizing radiation are poorly defined. Because the ms oncogene, a gene activated in many human cancers treated with radiotherapy, can induce increased radiore sistance, we have asked which Ras effector pathways are significant in conf erring a survival advantage to tumor cells. The phosphoinositide-3-kinase ( PI3K) inhibitor LY294002 radiosensitized cells bearing mutant ras oncogenes , but the survival of cells with wild-type ras was not affected. Inhibition of the PI3K downstream target p70S6K by rapamycin, the Raf-MEK-MAPK pathwa y with PD98059, or the Ras-MEK kinase-p38 pathway with SB203580 had no effe ct on radiation survival in cells with oncogenic I as. Expression of active PI3K in cells with wild-type ras resulted in increased radiation resistanc e that could be inhibited by LY294002, These experiments have indicated the importance of PI3K in mediating enhanced radioresistance and have implicat ed PI3K as a potential target for specific radiosensitization of tumors,