77P - Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer

Background

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease and new therapeutic strategies are urgently required. MCL1 is an anti-apoptotic BCL2 family member that promotes cancer cell survival, but its role in mCRPC remains poorly understood.

Methods

Here, we characterised MCL1 in multiple mCRPC biopsy cohorts and in patient-derived models, analysing functional and mechanistic responses of multiple models to MCL1 inhibition.

Results

First, MCL1 copy number gain was observed in 14-34% of lethal PCs, with this being associated with increased MCL1 RNA expression and worse clinical outcome. MCL1 inhibition exhibited anti-tumour effects in MCL1-gained mCRPC patient-derived xenograft organoids. Moreover, co-inhibition of MCL1 and AKT led to cancer-specific cell death in PTEN-loss/PI3K-activated models in vitro and in vivo through modulating BAD-BCLXL and BIM-MCL1 interactions, with durable anti-tumour activity in models with acquired resistance to AKT inhibition. Finally, CDK9-mediated MCL1 downregulation, combined with AKT inhibition, recapitulated these findings in vitro and in vivo, providing orthogonal validation and further opportunities for clinical translation of this therapeutic strategy.

Conclusions

These data support the evaluation of MCL1 targeting within ‘proof of concept, proof of mechanism’ early phase clinical trials, both as a single agent for MCL1 copy number gain mCRPC, and in combination with AKT inhibition in PTEN-loss/PI3K-activated mCRPC.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Prostate Cancer UK (TLD-PF19-006 to J.M.J-V.; Research Funding to J.S.dB.), National Cancer Institute/National Institutes of Health (R50CA274336, P50CA0907186, P01CA163227, and R21CA277368 to I.C. and P.S.N.; the Intramural Research Program of the Center for Cancer Research, Research Funding to W.D.), Medical Research Council (Research Funding to J.S.dB.), the Prostate Cancer Foundation (Young Investigator Award to S.W.; Challenge Award to S.P.B, J.S.dB. and A.S.), the Movember Foundation through the London Movember Centre of Excellence (CEO13 2-002 to J.S.dB.), the Wellcome Trust (Clinical Research Career Development Fellowship to A.S.), the Department of Defense Prostate Cancer Research Program (Early Investigator Research Award to S.W.; Impact Awards to A.G.S. and S.P.B.; Idea Development Award to A.G.S.), and Cancer Research UK (Centre Programme and Experimental Cancer Medicine Centre grants to J.S.dB.). Portions of this work was supported by the NCI (HHSN261200800001E), the Intramural Research Program of the NCI, NIH, and the NIH National Center for Advancing Translational Sciences. Portions of this work utilized the computational resources of the NIH HPC Biowulf cluster.

Disclosure

A.G. Sowalsky: Financial Interests, Personal, Funding: Astellas. P. Nelson: Financial Interests, Personal, Advisory Board, Consulting: Pfizer, Janssen; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Institutional, Funding: Oncternal; Financial Interests, Institutional, Research Grant: Janssen. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Menarini Silicon Biosystems, ImCheck Therapeutics, Crescendo, MetaCurUm, Myricx, Nurix Therapeutics, Oncternal Therapeutics; Financial Interests, Institutional, Advisory Board: Harpoon, Dark Blue Therapeutics, Novartis, Takeda, Tango Therapeutics; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi Sankyo, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics, Menarini Silicon Biosystems, Immunic Therapeutics, MetaCurUm, Myricx, Nurix Therapeutics, Oncternal Therapeutics; Financial Interests, Institutional, Invited Speaker: Amgen; Non-Financial Interests, Personal, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Crescendo, ImCheck Therapeutics, Immunic Therapeutics; Non-Financial Interests, Institutional, Product Samples: Daiichi Sankyo, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GSK. A. Sharp: Non-Financial Interests, Personal, Principal Investigator, Clinical trial in progress: AstraZeneca, Amgen, Exelixis, Nurix, Celcuity; Non-Financial Interests, Personal, Principal Investigator, Clinical trial in progress: Roche; Non-Financial Interests, Institutional, Product Samples, Access to IMP as a gift for research: AstraZeneca; Non-Financial Interests, Personal, Product Samples, Access to IMP as a gift for research: Cyclacel; Other, Personal, Other, Paid consultancy (to research): D.E Research, Charm Therapeutics, Ellipses, Doira; Other, Personal, Other, Paid for teaching session: MSD. All other authors have declared no conflicts of interest.