Developing therapeutic strategies to target MCL1 and BCLXL in lethal prostate cancer.

Targeting anti-apoptotic BCL2 family proteins is an attractive therapeutic strategy to drive prostate cancer (PCa) cell death. Here, we show that MCL1 is highly expressed in castration-resistant PCa, associating with worse clinical outcome. We demonstrate that targeting MCL1 with BH3 mimetics triggers apoptotic cell death in a subset of PCa cell line models. Furthermore, siRNA targeting of UCHL3, a deubiquitinating enzyme, downregulates MCL1 expression to synergize with BCLXL blockade; however, its impact on MCL1 is driven through an off-target effect, raising an important methodological consideration when studying MCL1 biology. Finally, we demonstrate that co-targeting MCL1 and BCLXL in patient-derived and mouse PCa models drives apoptotic PCa cell death. Taken together, targeting the intrinsic apoptosis pathway remains an attractive therapeutic strategy for lethal PCa. Future studies should focus on identifying strategies and technologies that can deliver cancer specific kill, to improve the outcome for men with this lethal disease.