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

Author

Listed:
  • Juan M. Jiménez-Vacas

    (The Institute of Cancer Research)

  • Daniel Westaby

    (The Institute of Cancer Research
    The Royal Marsden Hospital)

  • 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
    University of Cordoba; Reina Sofia University Hospital; CIBER Physiopathology of Obesity and Nutrition (CIBERobn))

  • 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
    Koc University)

  • Craig J. Thomas

    (National Institute of Health
    National Institutes 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
    The Royal Marsden Hospital)

  • Adam Sharp

    (The Institute of Cancer Research
    The Royal Marsden Hospital)

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.

Suggested Citation

  • 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 Lambro, 2025. "Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64042-5
    DOI: 10.1038/s41467-025-64042-5
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