Preclinical study using androgen receptor (AR) degradation enhancer to increase radiotherapy efficacy via targeting radiation-increased AR to better suppress prostate cancer progression

Background: While androgen deprivation therapy (ADT) and radiotherapy (RT) are currently used together to treat locally advanced prostate cancer (PCa), RT might have the adverse effect of increasing the PCa androgen receptor (AR) protein expression, which might then increase the resistance to continued RT. Methods: We used multiple assays for RT sensitivity, protein and RNA expression of AR and related DDR genes, ROS level, DNA damage/repair level, cell cycle and apoptosis. All statistical comparisons were analyzed with t-test or one-way ANOVA. Findings: We demonstrated that RT induced AR expression in C4-2 and CWR22Rv-1 cells. We found that combining RT and ASC-J9 (R), but not the antiandrogen, Enzalutamide, could increase radiosensitivity via inducing DNA damage, altering the AR mediated and DNA repair pathways, and activating apoptosis. ASC-J9 (R) had little effects on normal bladder cells. Interpretation: Targeting ionizing radiation (IR)-increased AR with the AR degradation enhancer, ASC-J9 (R), could increase the radiosensitivity while sparing adjacent normal tissue. Mechanism dissection revealed that ASC-J9 (R), but not Enzalutamide, treatment could increase radiosensitivity via inducing DNA damage, altering DNA repair pathways, as well as activating the IR-induced apoptosis via suppressing the pATR-CHK1 signals. Importantly, results from preclinical studies using an in vivo mouse model also demonstrated that combining RT with ASC-J9 (R) to target AR led to better therapeutic efficacy to suppress PCa progression. (C) 2019 The Authors. Published by Elsevier B.V.