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Implications of PI3K/AKT inhibition on REST protein stability and neuroendocrine prostate cancer Chen, Ruiqi

Abstract

Treatment-induced neuroendocrine (NE) prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that can arise as a consequence of rigorous androgen receptor pathway inhibition (ARPI) therapies now used to treat castration resistant disease (CRPC). While the PI3K/AKT pathway has been investigated as a co-therapeutic target with ARPI for advanced prostate adenocarcinoma, whether this strategy has implications on t-NEPC progression remains unknown. Findings from this work indicate that PI3K/AKT inhibition alone reduces protein expression of the RE-1 silencing transcription factor (REST) and induces multiple NE markers in PCa cells. The loss of REST by PI3K/AKT inhibition is through protein degradation mediated by the E3-ubiquitin ligase β-TRCP and REST phosphorylations at the S1024, S1027, and S1030 sites. Since AR inhibition was previously reported to deplete REST, results from this project reveal that the combined inhibition of PI3K/AKT and AR further aggravates REST protein reduction. Upon profiling the transcriptomes of AKT inhibition, AR inhibition, and AKT/AR co-inhibition in the LNCaP cell model, Gene Set Enrichment Analysis (GSEA) shows that these transcriptomes are highly correlated with the REST-regulated gene signature. Co-targeting AKT and AR resulted in an even higher correlation comparing to those of single treatment. Comparing these transcriptomes to the RNA-seq gene signature of t-NEPC patients by GSEA, it was observed that adding AKT inhibition to AR blockade enhanced the expression of neurogenesis-related genes and resulted in a stronger and broader upregulation of REST-regulated genes specific to t-NEPC. Collectively, these results indicate that AKT pathway inhibition can induce NE transdifferentiation in PCa cells via REST protein degradation. It delineates a potential risk for the AR and PI3K/AKT co-targeting strategy as it may further facilitate t-NEPC development.

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