Abstract 327: Targeting autophagy overcomes enzalutamide resistance in castrate-resistant prostate cancer cells and improves therapeutic response in a xenograft model

Abstract

Abstract Androgen deprivation or treatment with the androgen receptor signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) or biclutamide induces autophagy in androgen-dependent and castration resistant CaP (CRPC) cell lines. This autophagic process is mediated by AMPK activation and the suppression of mTOR through Raptor phosphorylation (Serine 792). Using autophagy modulators such as clomipramine (CMI) or metformin in combination with ENZA drastically reduces the cell survival in the colony formation assay. Metformin in combination with ENZA causes AR degradation, which is inhibited by proteasome inhibitor MG132. Transcriptome deep sequencing of parental and ENZA resistant C4-2B cells was carried out to examine differential gene expression pattern that may be related to their ability to survive under constant high exposure to ARSI. In-vivo studies with mice orthotopically implanted with ENZA resistant cells demonstrates that the combination of ENZA and autophagy modulators, CMI or metformin significantly reduces tumor growth when compared to control groups (p<0.005). Blocking autophagy pharmacologically or genetically significantly impairs prostate cancer cell survival in- vitro and in-vivo, implying the therapeutics potential of autophagy inhibitors in the antiandrogen resistance setting.This work is supported in part by Stand Up To Cancer - Prostate Cancer Foundation–Prostate Dream Team Translational Cancer Research Grant. This research grant is made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Citation Format: Joy C. Yang, Hao G. Nguyen, Hsing-Jien Kung, Xu-Bao Shi, Derya Tilki, Ralph W. deVere White, Allen C. Gao, Christopher P. Evans. Targeting autophagy overcomes enzalutamide resistance in castrate-resistant prostate cancer cells and improves therapeutic response in a xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 327. doi:10.1158/1538-7445.AM2014-327