A same‐day assay predicts apoptotic response to combined BCL‐2 and MCL‐1 BH3‐mimetic targeting in multiple myeloma cells

Grundy, Martin; Al?Kaisi, Firas; Cull, Joanna; Williams, Cathy; Smith, Dean; Seedhouse, Claire H.

Abstract

Recent advances in treatment options for multiple myeloma (MM) have positive impact on patient survival. However, there is a short fall of rapid and reliable assays that can predict patient response to novel agents. The anti-apoptotic proteins B-cell lymphoma-2 (BCL-2) and myeloid cell leukaemia-1 (MCL-1), are necessary for MM survival, although most myelomas are more dependent on MCL-1. BCL-2 inhibition alone yields significant cytotoxicity in only a minority of cases, therefore targeting both proteins simultaneously, is a therapeutic option. Venetoclax and S63845 are BCL-2 and MCL-1 targeting BH3-mimetics which have demonstrated apoptotic synergy in MM. We investigated whether a novel short-term flow cytometric cytochrome c release assay could predict response to dual BH3-mimetic targeting in MM cells. Six human myeloma cell lines (HMCL) and seven primary samples were treated with venetoclax and S63845 alone or in combination. The 4-hour assay confirmed the drug combination was synergistic in all HMCL tested. Annexin-V data at 48 hours corresponded with 4-hour response verifying the assay as a predictor of drug sensitivity. All primary samples responded to the drug combination, including samples with 1q gain and t(4;14) translocation. Normal stem cells were unaffected by the drug combination. We have developed a novel assay with the potential to predict response to therapy in MM cells.

Citation

Grundy, M., Al‐Kaisi, F., Cull, J., Williams, C., Smith, D., & Seedhouse, C. H. (2021). A same‐day assay predicts apoptotic response to combined BCL‐2 and MCL‐1 BH3‐mimetic targeting in multiple myeloma cells. eJHaem, 2(1), 40-47. https://doi.org/10.1002/jha2.133

• Journal Article Type: Article
• Acceptance Date: Nov 4, 2020
• Online Publication Date: Nov 20, 2020
• Publication Date: 2021-02
• Deposit Date: Jun 30, 2022
• Publicly Available Date: Jun 30, 2022
• Journal: eJHaem
• Electronic ISSN: 2688-6146
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 2
• Issue: 1
• Pages: 40-47
• DOI: https://doi.org/10.1002/jha2.133
• Public URL: https://nottingham-repository.worktribe.com/output/5065207
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/jha2.133