Abstract C61: The PI3K pathway inhibition in prostate cancer cells is enhanced by dual targeting with the mTOR inhibitor RAD001 and a mTOR/PI3K inhibitor leading to decreased cell proliferation and increased autophagy

摘要: Introduction: Metastatic prostate cancer patients often become resistant to standard treatments such as androgen ablation therapy and docetaxel treatment novel are needed. Loss of PTEN subsequent activation the PI3K pathway is common in with advanced cancer. However, use mTOR inhibitors rapamycin analogues single agents has had limited clinical impact identification a potent therapeutic strategy for inhibition remains critical question. Experimental procedures: We have used gene expression data generated from metastatic tumors collected both before after RAD001 along vitro experiments established cell lines determine TORC1 inhibition, kinase dual on signaling kinetics. Summary: Treatment decreased tumor levels pS6 but failed result response. Gene set enrichment analysis castration‐resistant biopsies prior following was associated increased activity treatment. Analysis downstream components PI3K/AKT showed reduced levels, minimal p4EBP1 phosphorylation AKT1. Cytotoxic synergy observed when combined inhibitor, LY294002 PI3K/mTOR inhibitors. These combinations more profound reduction resulting proliferation autophagy continued persistence pAKT. Reverse phase proteomics supports AKT an androgen‐receptor positive line treated combination multiple targets experience phosphorylation. Conclusion: results upregulation that inhibit demonstrate cytotoxic synergy. The manifestations these together persistent AKT. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C61.