While PANC 1, MIA PaCa 2, and Capan 2 cells weren’t radiosensitized t3m4 cells were radiosensitized by lapatinib. Lapatinib mediated radiosensitization happened in a dose dependent fashion and at doses impossible to have significant off-target effects. The ER of just one. 3 for T3M4 cells is in keeping with that described for known radiosensitizers such as gemcitabine or cisplatin. Suggestive natural compound library of the value of K ras mutations in the radiation reaction, T3M4 cells express wild type K ras while MIA PaCa 2, PANC Capan and 1 2 cell lines all express mutant K ras. The clear presence of constitutively active, mutant types of K ras, a molecular abnormality seen in approximately 9001-2000 of pancreatic cancers, has previously been shown to confer radioresistance. Thus, we hypothesized that inhibition of EGFR/HER2 signaling Cholangiocarcinoma by lapatinib with resulting radiosensitization was conferred through inhibition of specific downstream signaling pathways that are specifically stimulated in the presence of constitutively 1Baerman K, Caskey R, Sasi F, Earp H, Calvo B. EGFR/HER2 specific therapy inhibits development of pancreatic cancer cells. 2005 Gastrointestinal Cancers Symposium, 2005. p. Abst 84. 6 active Ras. We first evaluated the power of lapatinib to restrict downstream signaling of the Raf/MEK/ERK and PI3K/Akt pathways, two pathways with the capacity of being triggered by both Ras and EGFR/HER2. Activation of Akt, however not ERK1/2, was completely inhibited by lapatinib in the T3M4 cells, while neither ERK1/2 or Akt were inhibited by lapatinib in cells with mutant K ras. Taken together, these data claim that buy GW0742 resistance to lapatinib radiosensensitization in PANC 1, the MIA PaCa 2, and Capan 2 cells may be mediated by activation of PI3K/Akt by 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, however not exhibited sustained Akt activation, vector control and no change in ERK activation. This correlated with too little radiosensitization by lapatinib in cells expressing K ras, although not vector control. These support a model where the presence of mutant K ras can provide 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 observed with lapatinib mediated inhibition of EGFR/HER2 in the T3M4 cells, we reasoned that radiosensitization by lapatinib had been mediated by the inhibition of the downstream signaling pathway that is activated by both EGFR/HER2 and Ras.