biostudies-literatureJimenez-Vacas JMRoyal Society of MedicineProstate Cancer Foundation (PCF)Royal Society of Medicine (RSM)NCI NIH HHSProstate Cancer FoundationWellcome Trust8806https://www.ebi.ac.uk/biostudies/studies/S-EPMC12508096biostudies-literatureUnknown16(1)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. FinalNature communicationsElucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer.PMC12508096R50 CA274336Clinical Research Career Development FellowshipP01 CA163227R21 CA277368IES\R3\213131Challenge AwardGalipeau PLambros MBuroni LBertan CRiisnaes RTaylor JRekowski JSeed GBalk SPYuan WWelti JHa GJimenez-Vacas JMChau CHHobern EColeman IZeng WKarzai FThomas CJNeeb AJWilkinson SBezzi MCrespo MGabel FValenti MSharp APadilha ADas Sde Bono JSBogdan DCarreira SWaldron NWestaby DDe Haven Brandon ABeatson ELLiodaki KVarkaris ATrostel SYGurel BPersse TNelson PSSwain AParavati RRaynaud FFigueiredo IKlumpp-Thomas CPandell NFerreira ALuque RMMiranda SNing JMontero-Hidalgo AJFigg WDSowalsky AGBernett ILack NAZhang XYu IPLfalseElucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer.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. Final2025-01-01T00:00:00Z2025 Oct2026-06-04T09:25:49.395Z2026-05-07T03:12:33.052ZS-EPMC125080964106250010.1038/s41467-025-64042-5