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Potent efficacy of MCL-1 inhibitor-based therapies in preclinical models of mantle cell lymphoma

Oncogene volume 39, pages 2009–2023 (2020)Cite this article

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Abstract

Apoptosis-regulating BCL-2 family members, which can promote malignant transformation and resistance to therapy, have become prime therapeutic targets, as illustrated by the striking efficacy in certain lymphoid malignancies of the BCL-2-specific inhibitor venetoclax. In other lymphoid malignancies, however, such as the aggressive mantle cell lymphoma (MCL), cell survival might rely instead or also on BCL-2 relative MCL-1. We have explored MCL-1 as a target for killing MCL cells by both genetic and pharmacologic approaches. In several MCL cell lines, MCL-1 knockout with an inducible CRISPR/Cas9 system triggered spontaneous apoptosis. Accordingly, most MCL cell lines proved sensitive to the specific MCL-1 inhibitor S63845, and MCL-1 inhibition also proved efficacious in an MCL xenograft model. Furthermore, its killing efficacy rose on combination with venetoclax, the BCL-XL-specific inhibitor A-1331852, or Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which reduced pro-survival signals. We also tested the MCL-1 inhibitor in primary samples from 13 MCL patients, using CD40L-expressing feeder cells to model their microenvironmental support. Notably, all unstimulated primary MCL samples were very sensitive to S63845, but the CD40L stimulation attenuated their sensitivity. Mass cytometric analysis revealed that the stimulation likely conveyed protection by elevating BCL-XL and MCL-1. Accordingly, sensitivity of the CD40L-stimulated cells to S63845 was substantially restored by co-treatment with venetoclax, the BCL-XL-specific inhibitor or ibrutinib. Overall, our findings indicate that MCL-1 is very important for survival of MCL cells and that the MCL-1 inhibitor, both alone and together with ibrutinib, venetoclax or a BCL-XL inhibitor, offers promise for novel improved MCL therapies.

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Acknowledgements

We thank Naomi Sprigg (Royal Melbourne Hospital) for assistance with fresh clinical samples, Leonie Gibson and Tania Tan for excellent technical assistance, and Connie Li Wai Suen for statistical advice. We would like to acknowledge the Metro South Health Cancer Collaborative Biobank, Brisbane for the provision of hematologic malignancy samples for this project. The Cancer Collaborative Biobank is supported by Metro South Health funding. This work was supported by a CASS Foundation Science & Medicine Grant SM/18/7801 (to MAD); program grant 1016701 (to JMA) and Practitioner Fellowship 1079560 (to AWR) from the National Health and Medical Research Council (NHMRC); SCOR grant 7015-18 (to JMA and AWR) and Fellowship 5467-18 (to RT) from the Leukemia and Lymphoma Society; NHMRC Fellowship 1089072 (to CET), NHMRC Fellowship 1090236 (to DHG), Victorian Cancer Agency Fellowship MCRF 17028 (to GLK), Cancer Council of Victoria Grants-in-Aid 1146518 (to DHG) and 1147328 (to GLK), Leukaemia Foundation Australia grant (to GLK), and operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000220) and the Victorian State Government Operational Infrastructure Support Program. This work was performed in part at the Materials Characterization and Fabrication Platform at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility.

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  1. Ping Lan

    Present address: Institute for Advanced and Applied Chemical Synthesis, Jinan University, Zhuhai, Guangdong, 519070, China

Authors and Affiliations

  1. Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, Victoria, 3052, Australia

    Michael A. Dengler, Charis E. Teh, Rachel Thijssen, Lahiru Gangoda, Ping Lan, Marco J. Herold, Daniel H. Gray, Gemma L. Kelly, Andrew W. Roberts & Jerry M. Adams

  2. Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia

    Michael A. Dengler, Charis E. Teh, Rachel Thijssen, Lahiru Gangoda, Ping Lan, Marco J. Herold, Daniel H. Gray, Gemma L. Kelly, Andrew W. Roberts & Jerry M. Adams

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Contributions

MAD, GLK, AWR, and JMA designed research; MAD, CET, RT, LG, and PL performed experiments; MAD, CET, MJH, DHG, GLK, AWR, and JMA analyzed data; and MAD and JMA wrote the paper.

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Correspondence to Jerry M. Adams.

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All authors are employees of the Walter and Eliza Hall Institute, who receive milestone and royalty payments related to venetoclax. MJH, GLK, and AWR have received research funding from Servier.

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Dengler, M.A., Teh, C.E., Thijssen, R. et al. Potent efficacy of MCL-1 inhibitor-based therapies in preclinical models of mantle cell lymphoma. Oncogene 39, 2009–2023 (2020). https://doi.org/10.1038/s41388-019-1122-x

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