Abstract 3071: Improving the docetaxel-based chemotherapy in therapy resistance prostate cancer

Prostate cancer is known to have a relatively good prognosis, but long-term hormone therapy can lead to castration-resistant prostate cancer (CRPC). Docetaxel, a third-generation chemotherapy drug based on inhibiting depolymerization of microtubules, provide excellent initial response in patients for the CRPC treatment. Despite the improved survival duration and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. In this study, to elucidate the molecular basis of docetaxel resistance, we established docetaxel resistance prostate cancer PC3-TR, C4-2-TR and DU-145-TR cell lines, which exhibited higher LD50 and lower drug uptake against docetaxel than parental PC3, C4-2 and DU-145 cell lines. We employed quantitative high throughput screen with a collection of 2500 FDA approved drugs to identify drugs that can enhance the docetaxel sensitivity of docetaxel resistance cell lines. ML385 has been identified as a potent NF-E2 related factor-2 (Nrf2) synthetic inhibitor, and its treatment of docetaxel resistance cells significantly suppressed the Nrf2 signaling by decreasing the cytosolic and nuclear Nrf2 levels. In addition, docetaxel resistance cell lines showed marked increases in nuclear accumulation of Nrf2 compared to parental cell lines, suggesting that Nrf2 signaling is homeostatically activated in docetaxel resistance cell lines. Here we identified that silencing of Nrf2, docetaxel sensitivity of resistance cell lines was increased, and that of parental cell lines were reduced by activation of Nrf2. Combination treatment of ML385 with docetaxel induced cell death in docetaxel resistance cell lines. Together, these results provide new insight in the understanding of docetaxel resistance and direct a therapeutic approach to overcome docetaxel resistance in CRPC treatment. Citation Format: Md Rakibul Alam, Amos Olalekan Akinyemi, Jianlin Wang, Mithu Howlader, Lixiang Gu, Zhiguo Li. Improving the docetaxel-based chemotherapy in therapy resistance prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3071.