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Lymphoma

Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1

Leukemia volume 29, pages 1702–1712 (2015)Cite this article

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Abstract

Better treatments are needed for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of failing standard therapy. Avoiding apoptosis is a hallmark of cancer, and in DLBCL the redundantly functioning antiapoptotic proteins BCL2 and MCL1 are frequently expressed. Here we explore drugs that cause loss of MCL1, particularly the potent new cyclin-dependent kinase inhibitor dinaciclib, which knocks down MCL1 by inhibiting CDK9. Dinaciclib induces apoptosis in DLBCL cells but is completely overcome by increased activity of BCL2. We find that clinical samples have frequent co-expression of MCL1 and BCL2, suggesting that therapeutic strategies targeting only one will lead to treatment failures owing to activity of the other. The BH3 mimetic ABT-199 potently and specifically targets BCL2. Single-agent ABT-199 had modest antitumor activity against most DLBCL lines and resulted in compensatory upregulation of MCL1 expression. ABT-199 synergized strongly, however, when combined with dinaciclib and with other drugs affecting MCL1, including standard DLBCL chemotherapy drugs. We show potent antitumor activities of these combinations in xenografts and in a genetically accurate murine model of MYC-BCL2 double-hit lymphoma. In sum, we reveal a rational treatment paradigm to strip DLBCL of its protection from apoptosis and improve outcomes for high-risk patients.

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Acknowledgements

We thank Abbvie Inc. for provision of ABT-199 for this study and Associate Scientific Director Joel D. Leverson for advice on its use in vivo. We thank Bethany Skovan, Gillian Paine-Murrieta and Erica Sontz of the UACC Experimental Mouse Shared Resource for invaluable help with mouse studies. Funded by the NIH/NCI (P30CA023074-34 sub-award), the University of Arizona Bio5 Institute (JHS), the University of Arizona Cancer Center (JHS) and the Lymphoma Research Foundation (JHS).

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Authors and Affiliations

  1. Bio5 Institute, University of Arizona Cancer Center, Tucson, AZ, USA

    L Li, P Pongtornpipat & J H Schatz

  2. C,

    T Tiutan

  3. ollege of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA

    T Tiutan

  4. Department of Pathology, University of Arizona Cancer Center, Tucson, AZ, USA

    S L Kendrick & L M Rimsza

  5. Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA

    S Park, D O Persky, S D Puvvada & J H Schatz

  6. Department of Pharmacology and Toxicology, University of Arizona Cancer Center, Tucson, AZ, USA

    J H Schatz

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Li, L., Pongtornpipat, P., Tiutan, T. et al. Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1. Leukemia 29, 1702–1712 (2015). https://doi.org/10.1038/leu.2015.99

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