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Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer elicits improved anti-tumor efficacy and apoptosis

ABSTRACT: Both the PI3K/AKT/mTOR and androgen receptor (AR) signaling pathways play essential roles in prostate cancer. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and apoptosis induction, and observed the strongest effects in androgen-sensitive prostate cancer models. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, with most pronounced effects of the pan-PI3K inhibitor copanlisib. Transcriptomic analysis performed in the androgen-sensitive VCaP cell line revealed that gene expression was more affected by the co-treatment with darolutamide and copanlisib, compared to single agents. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs was observed. The combination treatment also markedly induced DNA damage. An in vivo efficacy study performed using LuCaP 35, an androgen-sensitive patient-derived prostate cancer model, indicated superior efficacy after combined treatment with copanlisib and darolutamide. Immunohistochemistry analysis of treated tumors furthermore showed increased apoptosis. Altogether these data demonstrate that blocking the PI3K/AKT/mTOR and AR pathways with potent inhibitors has superior anti-tumor efficacy and induces apoptosis in androgen-sensitive prostate cancer models.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245454 | GEO | 2024/01/22

REPOSITORIES: GEO

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Project description:Histone deacetylation is crucial for the regulation of chromatin structure, gene transcription and the epigenetic state of the cell. With the emergence of the neuroendocrine (NE) phenotype in castration-resistant prostate cancer (CRPC), we hypothesized that the inhibition of HDAC1/2 would disrupt the epigenetic events involved in the conversion of prostate adenocarcinoma to a NE prostate cancer (NEPC) phenotype. Additionally, monotherapies tend to have limited efficacy in cancer treatment and combination treatments show more promise. Since the PI3K/AKT/mTOR pathway is a well-established tumor growth-promoting pathway and a promising target in CRPC and NEPC, we investigated the tumor suppressing activities of fimepinostat, a dual HDAC and PI3K inhibitor, on both prostate adenocarcinoma and NEPC. We evaluated multiple cell lines and patient-derived xenograft (PDX) models of prostate adenocarcinoma and NEPC to determine the roles of HDAC1/2 and AKT inhibition, both individually and in combination, in suppressing CRPC and NEPC tumor growth in vitro and in vivo. HDAC1/2 inhibition in combination with PI3K/AKT inhibition was more efficacious than targeting each pathway alone, induced growth inhibitory effects (in some cases synergistic) through cell cycle inhibition and apoptosis across an array of prostate adenocarcinoma and NEPC patient-derived xenografts (PDX) and cell lines in vitro and in vivo. Molecular profiling revealed on-target effects of combined HDAC1/2 and PI3K/AKT inhibition as well as a common downregulation of Myc, E2F, DNA repair, and G2M checkpoint targets, independent of prostate cancer phenotype. Fimepinostat therapy was also associated with the suppression of lineage transcription factor expression including androgen receptor (AR) in prostate adenocarcinoma and Achaete-scute homolog 1 (ASCL1) in NEPC. Our findings demonstrate that dual HDAC1/2 and PI3K/AKT pathway inhibition leads to robust tumor growth inhibition in both adenocarcinoma and NEPC, suggesting that fimepinostat may represent a novel therapeutic for both prostate adenocarcinoma and NEPC phenotypes of CRPC.

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Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer elicits improved anti-tumor efficacy and apoptosis

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