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

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. RNA-seq of VCaP cells treated by DMSO control, synthetic androgen R1881, AR inhibitor sarolutamide, the pan-PI3K inhibitor copanlisib and their combination for 24 and 48 hours.