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

Despite the approval of multiple new therapies for advanced prostate cancer (PCa) over the past two decades, the disease remains invariably fatal. The development of new treatments for lethal PCa, with novel mechanisms of action, remains an unmet clinical need. One attractive strategy is to target the anti-apoptotic BCL2 family proteins, to breach the apoptotic threshold and drive PCa cell death. Here, we show that MCL1 RNA is highly expressed in castration-resistant PCa (CRPC), associating with signalling pathways linked to PCa progression, as well as with worse clinical outcome. In addition, we demonstrate that BH3 mimetics targeting MCL1 activate the intrinsic apoptosis pathway and drive cell death in a subset of PCa cell line models. Moreover, we identify that siRNA targeting of UCHL3, a deubiquitinating enzyme, downregulates MCL1 protein expression to synergise with BCLXL/BCL2 or BCLXL blockade in PCa cell line models; however, its impact on MCL1 is driven through an off-target effect of the siRNA seed region, raising an important methodological consideration when studying MCL1 biology. Importantly, we identify that loss of UCHL3 occurs in a significant subset of CRPC tissue biopsies and its expression associates with key signalling pathways in CRPC, warranting further investigation. Finally, we demonstrate that co-targeting MCL1 and BCLXL in patient-derived and mouse PCa models activates the intrinsic apoptosis pathway and drives 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.