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; Adam Sharp

doi:10.1038/s41467-025-64042-5

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 RekowskiRoberta 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^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	8806
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-64042-5
State	Published - Dec 2025

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Jiménez-Vacas, J. M., Westaby, D., Figueiredo, I., De Haven Brandon, A., Padilha, A., Yuan, W., Seed, G., Bogdan, D., Gurel, B., Bertan, C., Miranda, S., Lambros, M., Montero-Hidalgo, A. J., Coleman, I., Yu, I. P. L., Buroni, L., Zeng, W., Neeb, A. J., Welti, J., ... Sharp, A. (2025). Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer. Nature Communications, 16(1), Article 8806. https://doi.org/10.1038/s41467-025-64042-5

@article{2e8e6c20c33043888670e3d127242f9c,

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

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.",

author = "Jim{\'e}nez-Vacas, {Juan M.} and Daniel Westaby and Ines Figueiredo and {De Haven Brandon}, Alexis and Ana Padilha and Wei Yuan and George Seed and Denisa Bogdan and Bora Gurel and Claudia Bertan and Susana Miranda and Maryou Lambros and Montero-Hidalgo, {Antonio J.} and Ilsa Coleman and Yu, {Ivan Pak Lok} and Lorenzo Buroni and Wanting Zeng and Neeb, {Antje J.} and Jon Welti and Jan Rekowski and Roberta Paravati and Florian Gabel and Nicole Pandell and Ana Ferreira and Mateus Crespo and Ruth Riisnaes and Souvik Das and Joe Taylor and Nick Waldron and Emily Hobern and Melanie Valenti and Jian Ning and Ilona Bernett and Kate Liodaki and Thomas Persse and Patricia Galipeau and Scott Wilkinson and Trostel, {Shana Y.} and Fatima Karzai and Chau, {Cindy H.} and Beatson, {Erica L.} and Xiaohu Zhang and Carleen Klumpp-Thomas and Andreas Varkaris and Luque, {Raul M.} and Amanda Swain and Florence Raynaud and Lack, {Nathan A.} and Thomas, {Craig J.} and Gavin Ha and Figg, {William D.} and Marco Bezzi and Sowalsky, {Adam G.} and Nelson, {Peter S.} and Suzanne Carreira and Balk, {Steven P.} and {de Bono}, {Johann S.} and Adam Sharp",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-64042-5",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

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Jiménez-Vacas, JM, Westaby, D, Figueiredo, I, De Haven Brandon, A, Padilha, A, Yuan, W, Seed, G, Bogdan, D, Gurel, B, Bertan, C, Miranda, S, Lambros, M, Montero-Hidalgo, AJ, Coleman, I, Yu, IPL, Buroni, L, Zeng, W, Neeb, AJ, Welti, J, Rekowski, J, Paravati, R, Gabel, F, Pandell, N, Ferreira, A, Crespo, M, Riisnaes, R, Das, S, Taylor, J, Waldron, N, Hobern, E, Valenti, M, Ning, J, Bernett, I, Liodaki, K, Persse, T, Galipeau, P, Wilkinson, S, Trostel, SY, Karzai, F, Chau, CH, Beatson, EL, Zhang, X, Klumpp-Thomas, C, Varkaris, A, Luque, RM, Swain, A, Raynaud, F, Lack, NA, Thomas, CJ, Ha, G, Figg, WD, Bezzi, M, Sowalsky, AG, Nelson, PS, Carreira, S, Balk, SP, de Bono, JS & Sharp, A 2025, 'Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer', Nature Communications, vol. 16, no. 1, 8806. https://doi.org/10.1038/s41467-025-64042-5

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AU - Jiménez-Vacas, Juan M.

AU - Westaby, Daniel

AU - Figueiredo, Ines

AU - De Haven Brandon, Alexis

AU - Padilha, Ana

AU - Yuan, Wei

AU - Seed, George

AU - Bogdan, Denisa

AU - Gurel, Bora

AU - Bertan, Claudia

AU - Miranda, Susana

AU - Lambros, Maryou

AU - Montero-Hidalgo, Antonio J.

AU - Coleman, Ilsa

AU - Yu, Ivan Pak Lok

AU - Buroni, Lorenzo

AU - Zeng, Wanting

AU - Neeb, Antje J.

AU - Welti, Jon

AU - Rekowski, Jan

AU - Paravati, Roberta

AU - Gabel, Florian

AU - Pandell, Nicole

AU - Ferreira, Ana

AU - Crespo, Mateus

AU - Riisnaes, Ruth

AU - Das, Souvik

AU - Taylor, Joe

AU - Waldron, Nick

AU - Hobern, Emily

AU - Valenti, Melanie

AU - Ning, Jian

AU - Bernett, Ilona

AU - Liodaki, Kate

AU - Persse, Thomas

AU - Galipeau, Patricia

AU - Wilkinson, Scott

AU - Trostel, Shana Y.

AU - Karzai, Fatima

AU - Chau, Cindy H.

AU - Beatson, Erica L.

AU - Zhang, Xiaohu

AU - Klumpp-Thomas, Carleen

AU - Varkaris, Andreas

AU - Luque, Raul M.

AU - Swain, Amanda

AU - Raynaud, Florence

AU - Lack, Nathan A.

AU - Thomas, Craig J.

AU - Ha, Gavin

AU - Figg, William D.

AU - Bezzi, Marco

AU - Sowalsky, Adam G.

AU - Nelson, Peter S.

AU - Carreira, Suzanne

AU - Balk, Steven P.

AU - de Bono, Johann S.

AU - Sharp, Adam

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

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