Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer
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.
Article Details
Authors (58)
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
Vancouver Prostate Centre, Mohseni Institute of Urologic Science, University of British Columbia, 2660 Oak St, Vancouver, BC V6H 3Z6, Canada
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
State Key Laboratory of Critical Earth Material Cycling and Mineral Deposits, Nanjing University
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
National Center for Advancing Translational Sciences
Andreas Varkaris
Raul M. Luque
Amanda Swain
Florence Raynaud
Nathan A. Lack
Vancouver Prostate Centre, Mohseni Institute of Urologic Science, University of British Columbia, 2660 Oak St, Vancouver, BC V6H 3Z6, Canada
Craig J. Thomas
Gavin Ha
William D. Figg
Marco Bezzi
Adam G. Sowalsky
Peter S. Nelson
Division of Hematology and Oncology, University of Washington, Fred Hutchinson Cancer Center
Suzanne Carreira
Steven P. Balk
Department of Medicine, Beth Israel Deaconess Medical Center
Johann S. de Bono
Adam Sharp