Abstract B185: High efficacy of combination therapy of PI3K/AKT inhibitors with androgen deprivation in prostate cancer.

Abstract

Abstract Introduction and Objectives: A current challenge in prostate cancer (PCa) research is how to treat metastatic patients that have relapsed after androgen deprivation therapy. The PI3K/AKT pathway is frequently activated during PCa progression, with PTEN loss or mutation reported in up to 60% of advanced tumors, making it an interesting target for therapy. Recent reports have suggested a potential cross-talk between PI3K/AKT and androgen receptor (AR) pathway (1, 2). The present study aimed to assess the efficacy of combination therapy in PTEN-positive and PTEN-negative PCa models in vitro and in vivo and elucidate the mechanisms of interaction between both pathways. Material and Methods: The PI3K beta/delta inhibitor AZD8186 and AKT inhibitor AZD5363 were supplied by AstraZeneca (Macclesfield, UK). Growth response was tested in PTEN-positive (DU145 and VCAP) and PTEN-negative (LNCaP, PC346C, PC346Flu1 and PC346DCC) PCa cell lines by MTT assay. As response biomarkers, PI3K/AKT downstream targets phospho-AKT, phospho-PRAS40 and phospho-GSK3 were analyzed by western blotting. AR pathway activity was assessed by quantitative RT-PCR against AR, PSA, and TMPRSS2. Efficacy of both compounds was also tested in vivo in the PTEN-negative PC346C subcutaneous xenograft in combination with surgical castration. Results: AZD8186 and AZD5363 inhibited growth of all the PTEN-negative cell lines (LNCaP, PC346C, PC346Flu1, and PC346DCC) at nanomolar concentrations, while PTEN-positive cells were less sensitive (VCAP) or resistant (DU145). A dose dependent decrease in phosphorylation of AKT and its downstream targets was observed after treatment with AZD8186, which correlated with inhibition of cell growth. AZD5363 treatment resulted in increased AKT phosphorylation, as this compound stabilizes AKT in an inactive hyperphosphorylated state. Both AZD8186 and AZD5363 significantly inhibited in vivo growth of PC346C xenograft compared to that of placebo treated controls (respectively, 66% and 60% tumor growth inhibition after 28 days of treatment). Androgen depletion strongly increased the sensitivity to the PI3K/AKT inhibitors both in vitro and in vivo, with complete abrogation of tumor growth in castrated tumor-bearing mice. Additionally, up-regulation of AR signaling was observed after inhibition of the PI3K/AKT pathway, further lending support for cross-talk between both pathways. Conclusions: In conclusion, AZD8186 and AZD5363 efficiently targeted PI3K/AKT pathway and inhibited the growth of PTEN-negative PCa models in vitro and in vivo, particularly in combination with androgen depletion. These data suggest cross-talk between PI3K/AKT and AR pathways and indicate that for optimal antitumor efficacy inhibition of both pathways is required. The functional mechanisms underlying this cross-talk are the focus of our current research. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B185. Citation Format: Rute Marques, Ashraf Aghai, Debra Stuurman, Corrina de Ridder, Agnes Boer, Sander Hoeben, Jan Trapman, Wytske M. van Weerden. High efficacy of combination therapy of PI3K/AKT inhibitors with androgen deprivation in prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B185.