Dual downregulation of HRK and BAD promotes BCL-xL-mediated docetaxel resistance in prostate cancer

Prostate cancer is the second most common malignancy in men. For patients who present metastatic disease, androgen deprivation therapy is the standard of care. Despite significant initial responses to anti-androgenic therapy, almost all patients progress to an incurable metastatic castration-resistant prostate cancer, facing a significant therapeutic challenge. Docetaxel is a taxane that improves response rates in these patients, but its efficacy is limited due to the development of resistance, which can be mediated through anti-apoptotic adaptations. Dynamic BH3 profiling is a functional assay that can anticipate tumors’ anti-apoptotic adaptation to treatment and guide the use of specific inhibitors such as BH3 mimetics or PROTACs. In this study, we elucidate that BCL-xL is the major pro-survival protein in prostate cancer cell lines after docetaxel treatment, which can be reverted using BH3 mimetics or PROTAC strategies against this protein. We also describe for the first time that the downregulation of HRK and BAD sensitizer BH3-only proteins due to docetaxel treatment leads to BCL-xL mediated resistance in prostate cancer cells. Finally, we introduce a new functional technology that detects mitochondrial permeabilization, enabling successful testing of this therapeutic combination directly in patient‑derived prostate cancer cells.