Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer

Juan M. Jiménez-Vacas, Daniel Westaby, Ines Figueiredo, Alexis De Haven Brandon, Ana Padilha, Wei Yuan, George Seed, Denisa Bogdan, Bora Gurel, Claudia Bertan, Susana Miranda, Maryou Lambros, Antonio J. Montero-Hidalgo, Ilsa Coleman, Ivan Pak Lok Yu, Lorenzo Buroni, Wanting Zeng, Antje J. Neeb, Jon Welti, Jan Rekowski, Roberta Paravati, Florian Gabel, Nicole Pandell, Ana Ferreira, Mateus Crespo, Ruth Riisnaes, Souvik Das, Joe Taylor, Nick Waldron, Emily Hobern, Melanie Valenti, Jian Ning, Ilona Bernett, Kate Liodaki, Thomas Persse, Patricia Galipeau, Scott Wilkinson, Shana Y. Trostel, Fatima Karzai, Cindy H. Chau, Erica L. Beatson, Xiaohu Zhang, Carleen Klumpp-Thomas, Andreas Varkaris, Raul M. Luque, Amanda Swain, Florence 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 () and Adam Sharp ()
Additional contact information
Juan M. Jiménez-Vacas: The Institute of Cancer Research
Daniel Westaby: The Institute of Cancer Research
Ines Figueiredo: The Institute of Cancer Research
Alexis De Haven Brandon: The Institute of Cancer Research
Ana Padilha: The Institute of Cancer Research
Wei Yuan: The Institute of Cancer Research
George Seed: The Institute of Cancer Research
Denisa Bogdan: The Institute of Cancer Research
Bora Gurel: The Institute of Cancer Research
Claudia Bertan: The Institute of Cancer Research
Susana Miranda: The Institute of Cancer Research
Maryou Lambros: The Institute of Cancer Research
Antonio J. Montero-Hidalgo: The Institute of Cancer Research
Ilsa Coleman: Fred Hutchinson Cancer Center
Ivan Pak Lok Yu: University of British Columbia
Lorenzo Buroni: The Institute of Cancer Research
Wanting Zeng: The Institute of Cancer Research
Antje J. Neeb: The Institute of Cancer Research
Jon Welti: The Institute of Cancer Research
Jan Rekowski: The Institute of Cancer Research
Roberta Paravati: The Institute of Cancer Research
Florian Gabel: The Institute of Cancer Research
Nicole Pandell: The Institute of Cancer Research
Ana Ferreira: The Institute of Cancer Research
Mateus Crespo: The Institute of Cancer Research
Ruth Riisnaes: The Institute of Cancer Research
Souvik Das: The Institute of Cancer Research
Joe Taylor: The Institute of Cancer Research
Nick Waldron: The Institute of Cancer Research
Emily Hobern: The Institute of Cancer Research
Melanie Valenti: The Institute of Cancer Research
Jian Ning: The Institute of Cancer Research
Ilona Bernett: The Institute of Cancer Research
Kate Liodaki: The Institute of Cancer Research
Thomas Persse: Fred Hutchinson Cancer Center
Patricia Galipeau: Fred Hutchinson Cancer Center
Scott Wilkinson: National Institutes of Health
Shana Y. Trostel: National Institutes of Health
Fatima Karzai: National Institutes of Health
Cindy H. Chau: National Institutes of Health
Erica L. Beatson: National Institutes of Health
Xiaohu Zhang: National Institute of Health
Carleen Klumpp-Thomas: National Institute of Health
Andreas Varkaris: Beth Israel Deaconess Medical Center
Raul M. Luque: University of Cordoba; Reina Sofia University Hospital; CIBER Physiopathology of Obesity and Nutrition (CIBERobn)
Amanda Swain: The Institute of Cancer Research
Florence Raynaud: The Institute of Cancer Research
Nathan A. Lack: University of British Columbia
Craig J. Thomas: National Institute of Health
Gavin Ha: Fred Hutchinson Cancer Center
William D. Figg: National Institutes of Health
Marco Bezzi: The Institute of Cancer Research
Adam G. Sowalsky: National Institutes of Health
Peter S. Nelson: Fred Hutchinson Cancer Center
Suzanne Carreira: The Institute of Cancer Research
Steven P. Balk: Beth Israel Deaconess Medical Center
Johann S. de Bono: The Institute of Cancer Research
Adam Sharp: The Institute of Cancer Research

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64042-5

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