To determine if similar effects might be observed by inhibiting mTORC1 or MEK, we compared the effects of RAD001 LY364947 or PD0325901 to BEZ235, alone and in various combinations, including with MDV3100. The greatest antiproliferative effect was observed with combined treatment with BEZ235 and MDV3100, indicating that PI3K and/or mTORC1/2 and AR, but not mTORC1 or MEK, appear to be the most critical targets in this model. Based on our discovery that inhibition of the PI3K pathway promotes AR activity in a HER2/3 dependent manner, we reasoned that that a HER2/3 inhibitor might be similarly efficacious in combination with BEZ235. Indeed, combined treatment with BEZ235 and PKI166 was as effective as BEZ235 plus MDV3100.

Furthermore, inhibition of HER2/3 abolished Docetaxel ic50 the upregulation of AR protein levels and transcriptional activity observed with PI3K pathway inhibition, as measured by PSA expression. To test the impact of combined PI3K/AR therapy in tumor models, Ptenlox/lox mice with established prostate tumors were treated with BEZ235 + MDV3100 and castration. Combined PI3K and AR pathway inhibition led to dramatic reductions in tumor volume with near complete pathologic responses and no evidence of residual cell proliferation detectable by Ki67 staining. Combined PI3K/AR therapy also induced regressions in LNCaP xenografts whereas average tumor volume in mice treated with vehicle or single pathway therapy increased. Addition of BEZ235 to castration plus MDV3100 in PB MYC mice showed no measurable benefit, but the substantial response to combined androgen blockade alone in this model makes it difficult to detect any effect of Lymphatic system combined PI3K/AR therapy.

AR pathway inhibition has long been the treatment of choice for men with metastatic prostate cancer. Canagliflozin supplier While much attention has been devoted to mechanisms of acquired resistance, there has been little investigation of the considerable variability in primary response among patients. Here we show, by mRNA transcriptome analyses, that activation of the PI3K pathway is associated with repressed androgen signaling in mouse and human prostate cancers and that this may, in part, be responsible for the castrate resistant phenotype observed with these prostate tumors. Importantly, we demonstrate that this resistance is reversible because inhibition of the PI3K pathway restores AR signaling in PTEN deficient prostate cells. At least one mechanism appears to be through relief of negative feedback to HER kinases. Similarly, blockade of AR relieves feedback inhibition of AKT by the phosphatase PHLPP.