Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer

Abstract

Purpose The PI3K/Akt/mTOR pathway is activated in most castration-resistant prostate cancer (CRPC). Transcriptionally active androgen receptor (AR) plays a role in the majority of CRPC. Therefore, co-targeting full-length (FL) AR and PI3K/Akt/mTOR signaling has been proposed as a possible more effective therapeutic approach for CRPC. However, truncated AR-splice variants (AR-Vs) that are constitutively active and dominant over FL-AR are associated with tumor progression and resistance mechanisms in CRPC. It is currently unknown how blocking the PI3K/Akt/mTOR pathway impacts prostate cancer driven by AR-Vs. Here we evaluated the efficacy and mechanism of combination therapy to block mTOR activity together with EPI-002, an AR N-terminal domain (NTD) antagonist that blocks the transcriptional activities of FL-AR and AR-Vs in models of CRPC. Experimental design To determine the functional roles of FL-AR, AR-Vs and PI3K/Akt/mTOR pathways, we employed EPI-002 or enzalutamide and BEZ235 (low dose) or everolimus in human prostate cancer cells that express FL-AR or FL-AR and AR-Vs (LNCaP95). Gene expression and efficacy were examined in vitro and in vivo. Results EPI-002 had antitumor activity in enzalutamide-resistant LNCaP95 cells that was associated with decreased expression of AR-V target genes (e.g., UBE2C). Inhibition of mTOR provided additional blockade of UBE2C expression. A combination of EPI-002 and BEZ235 decreased the growth of LNCaP95 cells in vitro and in vivo. Conclusion Co-targeting mTOR and AR NTD to block transcriptional activities of FL-AR and AR-Vs provided maximum antitumor efficacy in PTEN-null, enzalutamide resistant CRPC.

Thapsigargin induces apoptosis of prostate cancer through cofilin‑1 and paxillin

“…The present study indicated that thapsigargin significantly decreased cell proliferation, and increased the apoptosis rate and caspase-9/3 activities in PC3 cells. The mTOR signal transduction pathway primarily participates in the synthesis of proteins (20). A previous study concerning the suspected associations between single nucleotide polymorphisms in the signal transduction pathway gene and prostate cancer conducted worldwide (21).…”

“…mTOR is widely expressed in cells and regulates multiple cellular functions in different cells, including survival and proliferation (21). On the one hand, the mammalian target of rapamycin complex 1 regulates translation, including 5'terminal oligopyrimidine tract mRNAs (20). Conversely, mTORC1 serves as the central pivot of the cascade signal channel that regulates RNA translation.…”

Non-Genomic Actions of the Androgen Receptor in Prostate Cancer

“…Concurrent inhibition of AR and non-genomic AR components may prove useful for prostate cancer patients with progression after primary therapy. Many of these strategies are currently under investigation and show promising results in preclinical models of CRPC (82–85). …”

Emerging data on androgen receptor splice variants in prostate cancer

“…Here, we describe several AR-V-targeting agents that have entered clinical trials for cancer treatment. EPI-001/002 is a small-molecule, non-steroidal AR antagonist that covalently binds to AR N-terminal domain to inhibit the transcriptional activities of AR-FL and AR-Vs (Andersen, et al 2010; Kato, et al 2016; Myung et al 2013; Sadar 2011). It has also been found to act as a selective PPARγ modulator to inhibit AR expression (Brand, et al 2015).…”