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Multiple myeloma, gammopathies

Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma

Leukemia volume 32, pages 2224–2239 (2018)Cite this article

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Abstract

Bromodomain and extraterminal (BET) domain containing protein (BRD)-4 modulates the expression of oncogenes such as c-myc, and is a promising therapeutic target in diverse cancer types. We performed pre-clinical studies in myeloma models with bi-functional protein-targeting chimeric molecules (PROTACs) which target BRD4 and other BET family members for ubiquitination and proteasomal degradation. PROTACs potently reduced the viability of myeloma cell lines in a time-dependent and concentration-dependent manner associated with G0/G1 arrest, reduced levels of CDKs 4 and 6, increased p21 levels, and induction of apoptosis. These agents specifically decreased cellular levels of downstream BRD4 targets, including c-MYC and N-MYC, and a Cereblon-targeting PROTAC showed downstream effects similar to those of an immunomodulatory agent. Notably, PROTACs overcame bortezomib, dexamethasone, lenalidomide, and pomalidomide resistance, and their activity was maintained in otherwise isogenic myeloma cells with wild-type or deleted TP53. Combination studies showed synergistic interactions with dexamethasone, BH3 mimetics, and Akt pathway inhibitors. BET-specific PROTACs induced a rapid loss of viability of primary cells from myeloma patients, and delayed growth of MM1.S-based xenografts. Our data demonstrate that BET degraders have promising activity against pre-clinical models of multiple myeloma, and support their translation to the clinic for patients with relapsed and/or refractory disease.

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Acknowledgements

This work was supported by funding from The MD Anderson Cancer Center Knowledge Gaps program, The MD Anderson Cancer Center Moon Shot in High Risk Multiple Myeloma, the National Cancer Institute (The MD Anderson Cancer Center SPORE in Multiple Myeloma (P50 CA142509) and R01s CA184464 and CA194264), the Leukemia & Lymphoma Society (New Idea Award 8994-12 and Specialized Center of Research SCOR-12206-17), the National Natural Science Foundation of China (Grant 81600170), and a Jiangsu government scholarship for overseas studies (JS-2014-195). The authors would like to thank the MD Anderson Flow Cytometry and Cellular Imaging Core Facility and the Characterized Cell Line Core Facility, which are supported by the Cancer Center Support Grant (P30 CA16672). R.Z.O. would also like to acknowledge support from the Florence Maude Thomas Cancer Research Professorship, the Brock Family Myeloma Research Fund, and the Jean Clarke High-risk Myeloma Research Fund.

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Author notes

  1. Jing Lu

    Present address: Ideaya Biosciences, San Diego, CA, USA

  2. These authors contributed equally: Xiaohui Zhang, Hans C. Lee, Fazal Shirazi.

Authors and Affiliations

  1. Department of Hematology, Second Affiliated Hospital of Soochow University, Suzhou City, China

    Xiaohui Zhang

  2. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Xiaohui Zhang, Hans C. Lee, Fazal Shirazi, Isere Kuiatse, Hua Wang, Richard J. Jones, Zuzana Berkova, Ram Kumar Singh, Bingzong Li, Huihan Wang, Sheeba K. Thomas, Zhiqiang Wang, R. Eric Davis & Robert Z. Orlowski

  3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Veerabhadran Baladandayuthapani & Heather Lin

  4. Arvinas, LLC, New Haven, CT, USA

    Jing Lu, Yimin Qian, Kanak Raina & Kevin G. Coleman

  5. Deptartment of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA

    Craig M. Crews

  6. Department of Chemistry, Yale University, New Haven, CT, USA

    Craig M. Crews

  7. Department of Pharmacology, Yale University, New Haven, CT, USA

    Craig M. Crews

  8. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yared Hailemichael

  9. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Robert Z. Orlowski

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Contributions

XZ planned and conducted most of the experiments, analyzed the results, and drafted the manuscript. HCL planned and conducted experiments, analyzed results, and revised the manuscript. FS planned and conducted experiments and analyzed results. VB and HL performed statistical analyses and interpreted the data. IK, FS and YH performed animal experiments, while RJJ, JL, and YQ participated in the design and analysis of experiments. SKT and HCL provided primary samples, BL and HW with HCL provided cell lines, while RED performed gene expression analysis. RKS performed immunohistochemistry and immunofluorescence studies. ZB helped analyze the data and draft the manuscript. KR and KGC reviewed the data and the manuscript. CMC helped develop the PROTACs. RZO conceived of the line of investigation, designed the experiments, analyzed the results, and edited the manuscript.

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Correspondence to Robert Z. Orlowski.

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Conflict of interest

RZO has served on advisory boards for Amgen, which manufactures and distributes carfilzomib, Takeda Pharmaceuticals USA, Inc., which manufactures and distributes bortezomib, and for Celgene Corporation, which manufactures and distributes lenalidomide and pomalidomide, but there was no commercial support for this research. JL, YQ, KR, and KGC are employees of Arvinas, LLC, which manufactures the PROTACs studied in this work. CMC is founder, consultant and shareholder of Arvinas, LLC. In addition, his lab receives research funding from Arvinas, LLC. The remaining authors have no conflicts of interest to declare.

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Zhang, X., Lee, H.C., Shirazi, F. et al. Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia 32, 2224–2239 (2018). https://doi.org/10.1038/s41375-018-0044-x

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