Hierarchy for targeting pro-survival BCL2 family proteins in multiple myeloma: pivotal role of MCL1
- Gong, JN; Khong, T; Segal, D; Yao, Y; Riffkin, CD; GARNIER, JM; Khaw, SL; Lessene, G; Spencer, A; Herold, MJ; Roberts, AW; Huang, DC;
- Journal Title
- Publication Type
- Journal Article
- New therapeutic targets are needed to address the poor prognosis of patients with high-risk multiple myeloma. Myeloma cells usually express a range of the pro-survival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines using pharmacological inhibitors, gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or low-passage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized sub-set of myeloma that is highly BCLXL-dependent, and the potential for co-targeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high quality, validated inhibitors become available.
- WEHI Research Division(s)
- Cancer And Haematology; Chemical Biology; Molecular Genetics Of Cancer
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- Publisher's Version
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Creation Date: 2016-08-10 04:12:53Last Modified: 2018-07-11 09:22:23