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
2025-10-08
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.