Juan M. Jiménez-Vacas, Daniel Westaby, Ines Figueiredo, Alexis de Haven Brandon, Ana Padilha, Wei Yuan, George Seed, Denisa Bogdan, Bora Gürel, Claudia Bertan, Susana Miranda, Maryou B. Lambros, Antonio J. Montero‐Hidalgo, Ilsa M. Coleman, Ivan Pak Lok Yu, Lorenzo Buroni, Wanting Zeng, Antje Neeb, Jon Welti, Jan Rekowski, Roberta Paravati, Florian Gabel, Nicole Pandell, Ana Ferreira, Mateus Crespo, Ruth Riisnaes, Souvik Das, John D. Taylor, Nick Waldron, Emily Hobern, Melanie Valenti, Jian Ning, Ilona Bernett, Kate Liodaki, Thomas Persse, Patricia C. Galipeau, Scott Wilkinson, Shana Y. Trostel, Fatima Karzai, Cindy H. Chau, Erica L. Beatson, Xiaohu Zhang, Carleen Klumpp‐Thomas, Andreas Varkaris, Raúl M. Luque, Amanda Swain, Florence I. Raynaud, Nathan A. Lack, Craig J. Thomas, Gavin Ha, William D. Figg, Marco Bezzi, Adam G. Sowalsky, Peter S. Nelson, Suzanne Carreira, Steven P. Balk, Johann S. de Bono, Adam Sharp
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease requiring additional therapeutic strategies. MCL1, an anti-apoptotic BCL2 family member, promotes cancer-cell survival, but its role in mCRPC remains poorly understood. Here, we characterise MCL1 in multiple mCRPC biopsy cohorts and patient-derived models, assessing responses to MCL1 inhibition. MCL1 copy number gain (14%-34%) correlates with increased MCL1 expression and worse outcomes. MCL1 inhibition exhibits anti-tumour effects in MCL1-gained mCRPC models. Co-inhibition of MCL1 and AKT induces cancer-specific cell death in PTEN-loss/PI3K-activated models in vitro and in vivo, modulating BAD-BCLXL and BIM-MCL1 interactions, with durable anti-tumour activity in models with AKT inhibitor acquired resistance. Finally, CDK9-mediated MCL1 downregulation combined with AKT inhibition recapitulates these findings, providing further opportunities for clinical translation. These data support early phase clinical trials targeting MCL1, both as monotherapy for MCL1-gained mCRPC, and in combination with AKT inhibition for PTEN-loss/PI3K-activated mCRPC.