Effects of NVP BKM120 are specific for PI3K inhibition Given the un expected and striking effects of the pan Class IA PI3K inhibitor, NVPBKM120 BAY 11-7821 to the DNA damage response, we questioned if these effects were specific to a single Class IA PI3K isoform or required inhibition of multiple PI3Ks or could be an off target effect of NVP BKM120. In the BRCA1 mutant cell line SUM149 down-regulation of PI3K, but not PI3KB, with siRNA led to a stark boost in phosphorylation of DNA PK, H2AX and poly ribosylation and a stark decrease in accumulation. These data confirm that it is the inhibition of PI3K that is decisive for your disruption of the DNA damage response in these cells. Therapeutic effectiveness of PI3K inhibitor NVP BKM120 alone and in conjunction with the PARP Inhibitor Olaparib We first examined the effect of NVP BKM120 and Olaparib on the development on plastic of the two BRCA1 mutant cell lines. HCC1937 cells, with a genetic loss of PTEN, confirmed greater sensitivity to NVP BKM120 than SUM149 cells, which have wild type PTEN. SUM149, to the other-hand, confirmed greater sensitivity to Olaparib. The drug combination didn’t have much advantage DNA-dependent RNA polymerase beyond that of the most powerful single agent in either cell line and isogenic reconstitution of PTEN in HCC1937 did not substantially alter drug sensitivities, indicating that underneath the artificial conditions of growth on plastic with high levels of nutrients and oxygen, and in the absence of the indigenous cancer micro-environment, this drug combination doesn’t end up in synergy. We next resolved whether Olaparib and NVP BKM120 might have a more remarkable effect in vivo, on endogenous BRCA1 wiped cancers. We first showed that, consistent with the observations with the human BRCA1 mutant cell lines, NVP BKM120 treatment of Aurora B inhibitor rats with BRCA1 deleted chest tumors resulted in a increase in phosphorylated H2AX within the recurrent tumors. We next compared the effects of NVP BKM120 and Olaparib as individual agents and the mixture of both drugs on tumefaction growth. Female virgin MMTV CreBRCA1f/fp53 mice were observed for the development of spontaneous tumors, which an average of occurs at age 8 12 months. Rats were randomized to either vehicle control treatments, treatments with NVP BKM120 via oral gavage, Olaparib intraperitoneally, or even the mixture of NVP BKM120 with Olaparib, all once every day constantly, once tumors reached a length of 5 7 mm. A preliminary set of rats was handled with NVP BKM120 at 50 mg/kg/day, alone or in combination with Olaparib and another set at NVP BKM120 30 mg/ kg/day alone or in combination with Olaparib. No factor was seen pertaining to efficacy or p AKT suppression between your two dose ranges of NVPBKM120 and data were pooled. Tumors were measured at least 3 times per week, and relative tumor volume, being a ratio to standard tumor volume, was calculated for every treatment modality.