Work

PD32-10 PHOSPHORYLATION OF AMPKα AT SER-485/491 IS ASSOCIATED WITH METASTASIS AND CASTRATION-RESISTANCE IN PROSTATE CANCER: A CLINICAL STUDY

Year: 2016

Type: article

Abstract: INTRODUCTION AND OBJECTIVES: Several drugs targeting the androgen-signaling pathway or PI3K-AKT-mTOR pathway are in clinical trails for prostate cancer (PCa).Despite promise drugs such as RAD001 have not shown dramatic affectivity in clinical trials.This is perhaps due to a feedback loop that exits between the AR-and PI3K-AKT pathways.Combining drugs is an effective way of overcoming signaling cross talks, increasing efficacy and reducing resistance development.Towards this, a systematic and detailed analysis of the combined effects of the drugs targeting the 2 pathways needs to be carried out.Here, we investigated the combination effects of MDV3100 (AR antagonist), BKM120 (PI3K inhibitor), TKI258 (pan RTK inhibitor) and RAD001 (mTOR inhibitor) in several PCa cell lines.We further tested the effect of combining these drugs with a chemotherapy drug, cabazitaxel.METHODS: Cultured prostate cancer cell lines, LNCaP, PC3 and CWR22RV1 were treated singly or with 2-drug combinations and cell-viability measured.From the viability data, combination index (CI) of the different inhibitors was calculated using the Compusyn software.CI of <1 denotes synergy, 1 additive and >1 antagonism.RESULTS: All the inhibitors were able to inhibit cell growth as single-agent treatment in the compatible cell lines.Strong synergy however, was observed when AR+ LNCaP cells were treated with MDV3100 in combination with any one of PI3K-AKT-mTOR inhibitors.Variable levels of synergism was observed when either of the prostate cancer cells, LNCaP, PC3 or CWR22RV1, were treated with a combination of any two PI3K-Akt-mTOR pathway inhibitors with CI values ranging from 0.25 -0.93.Synergy was also observed when any of the targeted-therapy drugs was combined with cabazitaxel, (see Table 1).CONCLUSIONS: Our in vitro data suggests that combination of AR-and PI3K-AKT pathway inhibitors, or combination of two separate inhibitors targeting the PI3K-AKT pathway, or any of the targeted therapy drugs with cabazitaxel, provides variable levels of synergy.The best synergy was observed with MDV-RAD followed by MDV-BKM.No antagonism was observed with any drug combination.

Source: The Journal of Urology

DOI: 10.1016/j.juro.2016.02.686