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<p>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. <i>MCL1</i> copy number gain (14%–34%) correlates with increased MCL1 expression and worse outcomes. MCL1 inhibition exhibits anti-tumour effects in <i>MCL1</i>-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 <i>MCL1</i>-gained mCRPC, and in combination with AKT inhibition for PTEN-loss/PI3K-activated mCRPC.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月8日

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  • 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,
  • Adam Sharp

摘要

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.