T3M4 cells were radiosensitized by lapatinib while MIA PaCa 2, PANC 1, and Capan 2 cells weren’t radiosensitized. Lapatinib mediated radiosensitization happened in a dose dependent manner and at doses unlikely to have significant off-target results. The ER of just one. 3 for T3M4 cells is consistent with that described for known radiosensitizers including gemcitabine or cisplatin. Suggestive ATP-competitive HCV protease inhibitor of the value of K ras mutations in the light reaction, T3M4 cells express wild-type K ras while MIA PaCa 2, PANC 1 and Capan 2 mobile lines all express mutant K ras. The presence of constitutively active, mutant types of E ras, a molecular problem noticed in about 3 months of pancreatic cancers, has previously been shown to confer radioresistance. Thus, we hypothesized that inhibition of EGFR/HER2 signaling Cellular differentiation by lapatinib with resulting radiosensitization was conferred through inhibition of specific downstream signaling pathways that are directly stimulated in the existence of constitutively 1Baerman K, Caskey L, Sasi F, Earp H, Calvo B. EGFR/HER2 precise treatment inhibits growth of pancreatic cancer cells. 2005 Gastro-intestinal Cancers Symposium, 2005. p. Abst 84. 6 active Ras. We first examined the ability of lapatinib to restrict downstream signaling of the PI3K/Akt and Raf/MEK/ERK pathways, two pathways capable of being activated by both EGFR/HER2 and Ras. Activation of Akt, although not ERK1/2, was totally inhibited by lapatinib inside the T3M4 cells, while neither ERK1/2 nor Akt were inhibited by lapatinib in cells with mutant E ras. Taken together, these data claim that BAY 11-7821 resistance to lapatinib radiosensensitization in PANC 1, the MIA PaCa 2, and Capan 2 cells may be mediated by activation of PI3K/Akt by mutant Ras. K ras expression blocks radiosensitization by lapatinib To look for the role of mutant Ras in conferring radioresistance in these cells, we next evaluated whether ectopic expression of mutant K ras could abrogate lapatinib mediated radiosensitization of T3M4 cells. Cells treated with lapatinib that have been expressing K ras, although not vector control, exhibited sustained Akt activation and no change in ERK activation. This correlated with too little radiosensitization by lapatinib in cells expressing K ras, however not vector control. These support a model when the presence of mutant K ras can establish pancreatic cancer cells resistant to lapatinibmediated radiosensitization. Pancreatic cancer cells are radiosensitized by inhibition of PI3K/Akt, but not MEK/ERK If activated Ras could block the radiosensitization noticed with lapatinib mediated inhibition of EGFR/HER2 within the T3M4 cells, we reasoned that radiosensitization by lapatinib was being mediated by the inhibition of a downstream signaling pathway that’s activated by both EGFR/HER2 and Ras.