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Multiple myeloma gammopathies

BCL2 blockade overcomes MCL1 resistance in multiple myeloma

Leukemia volume 33, pages 2098–2102 (2019)Cite this article

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Disruption of the intrinsic apoptotic pathway by the aberrant expression of the BCL2 family members are frequent events in multiple myeloma (MM). In particular, the anti-apoptotic protein myeloid cell leukemia-1 (MCL1) is highly expressed in MM and plays a crucial role in disease progression [1, 2]. Using an unbiased approach to analyze cell death clustering, Gomez-Bougie and colleagues recently identified a group of MM patients insensitive to all the three classes of BH3 mimetics targeting MCL1, BCL2, and BCLxL. These BH3 mimetic-resistant patients were mostly found at diagnosis, and they often do not possess any recurrent chromosomal translocations. BCL2 dependency is mainly found in patients with t(11;14) CCND1 translocation. BCLxL dependency is rare in MM as they are often co-dependent on either BCL2 or MCL1. MCL1 dependency was strikingly predominant at relapse and in patients lacking common translocations and in the CCND1 subgroup. These findings suggested a shift of cellular plasticity towards MCL1 dependence during disease progression as a result of prior treatments or clonal selection [3].

A majority of well-established human MM cell lines and low-passage patient-derived myeloma cell lines have been shown to be MCL1 dependent using pharmacological inhibitors or gene editing approaches that specifically target MCL1 [4]. Clinically, overexpression of MCL1 is observed in 52% of MM patients at diagnosis and 81% at relapse. The level of MCL1 expression correlates with disease progression, and a higher MCL1 expression is associated with shorter survival [5]. Since MM is heavily reliant on MCL1, MM patients, particularly those at relapse, would benefit from an MCL1-targeted therapy. However, there is no FDA-approved drug with the ability to selectively target MCL1. To address this unmet medical need, a few selective MCL1 inhibitors are currently being developed in preclinical phase or clinical trials and have thus far shown promising results as single agents or used in combination with established therapies in various cancers, particularly in hematologic malignancies [6,7,8]. To further explore MCL1 biology in MM, we use a clinical-grade small-molecule MCL1 inhibitor, AZD5991, to investigate the mechanistic underpinning of MCL1 inhibition in MM.

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Acknowledgements

This work is supported by the Multiple Myeloma Research Fund at the Massachusetts General Hospital. AstraZeneca provided the AZD5991 compound. The authors would like to thank the Flow, Image, and Mass Cytometry Core in the Department of Pathology at the Massachusetts General Hospital for their support in cell sorting and flow cytometry analysis.

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Authors and Affiliations

  1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA

    Ka Tat Siu, Cristina Panaroni, Kenta Mukaihara, Keertik Fulzele, Rosemary Soucy, Cassandra Thorburn & Noopur Raje

  2. Broad Institute, Cambridge, MA, 02142, USA

    Cherrie Huang & Shrikanta Chattopadhyay

  3. Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Boston, MA, USA

    Justin Cidado & Lisa Drew

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Contributions

K.T.S., S.C., and N.R. designed the research; K.T.S. and C.H. performed the research; K.T.S., C.H., C.P., K.M., K.F., R.S., C.T., S.C., and N.R. analyzed the data; J.C. and L.D. provided the AZD5991 compound; K.T.S. and N.R. wrote the manuscript; and all the authors reviewed the manuscript.

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Correspondence to Noopur Raje.

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Conflict of interest

J.C. and L.D. are employees of AstraZeneca. N.R. is on advisory boards of Amgen, Bristol-Myers Squibb, Celgene, Merck, Janssen and Takeda. N.R. has received research funding from AstraZeneca. The remaining authors declare that they have no conflict of interest.

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Siu, K.T., Huang, C., Panaroni, C. et al. BCL2 blockade overcomes MCL1 resistance in multiple myeloma. Leukemia 33, 2098–2102 (2019). https://doi.org/10.1038/s41375-019-0421-0

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