Abstract 1517: AKT inhibition induces neuroendocrine phenotype in prostate cancer cells

Abstract

Abstract Androgen receptor (AR) signaling pathway inhibition (ARPI) is the primary treatment for locally advanced, recurrent, or metastatic prostate cancer. While ARPI is effective in short term, a fatal relapse is inevitable. The AKT signaling pathway inhibition has been investigated under multiple ongoing clinical trials as a co-therapeutic target with ARPI. The AKT signaling pathway is targeted due to its role in tumorigenesis, prevalent over-activation, and reciprocal activation upon ARPI in prostate cancer. However, this novel combination therapy may in fact facilitate PCa to progress into one of the most lethal subtypes called neuroendocrine (NE) prostate cancer (NEPC). Specifically, evidence has shown that ARPI contributes to NEPC progression at least in part by down-regulating the expression of RE-1 Silencing Transcription Factor (REST). Loss of REST is a hallmark of NEPC progression because REST functions as a negative master regulator in neurogenesis by suppressing genes required for neural differentiation. Similar to ARPI, our studies found that AKT inhibition reduced REST protein expression and increased NEPC markers in multiple prostate cancer cell lines. We also showed that the loss of REST upon AKT inhibition was through protein degradation mediated by an E3-ubiquitin ligase TRCP, which recognizes a phosphorylated REST degron region to recruit ubiquitins. In vivo ubiquitination assays confirmed the elevated REST ubiquitination after the treatment of PI3K inhibitors. Furthermore, mutations within the REST degron region reversed the TRCP-mediated REST ubiquitination and degradation. Finally, co-treatment of AKT pathway inhibition and ARPI showed aggravated REST depletion and increased NE markers in the prostate cancer cell line LNCaP. Collectively, these findings indicate that AKT pathway inhibition can induce NE phenotype in prostate cancer cells via REST protein degradation. This study may provide a caution to the ARPI/AKT co-target strategy as this strategy can potentially facilitate NEPC development. Citation Format: RuiQi Chen, Yinan Li, Xuesen Dong. AKT inhibition induces neuroendocrine phenotype in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1517. doi:10.1158/1538-7445.AM2017-1517