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The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma

Oncogene volume 37, pages 1830–1844 (2018)Cite this article

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Abstract

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, mostly known as double-hit lymphoma (DHL), is a rare entity characterized by morphologic and molecular features between Burkitt lymphoma and the clinically manageable diffuse large B-cell lymphoma (DLBCL). DHL patients usually undergo a rapidly progressing clinical course associated with resistance to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival inferior to 1 year. ABT-199 (venetoclax) is a potent and selective small-molecule antagonist of BCL-2 recently approved for the treatment of a specific subtype of lymphoid neoplasm. In this study, we demonstrate that single-agent ABT-199 efficiently displaces BAX from BCL-2 complexes but fails to maintain a significant antitumor activity over time in most MYC+/BCL2+DHL cell lines and primary cultures, as well as in a xenograft mouse model of the disease. We further identify the accumulation of the BCL2-like protein BFL-1 to be a major mechanism involved in acquired resistance to ABT-199. Noteworthy, this phenomenon can be counteracted by the BET bromodomain inhibitor CPI203, since gene expression profiling identifies BCL2A1, the BFL-1 coding gene, as one of the top apoptosis-related gene modulated by this compound. Upon CPI203 treatment, simultaneous downregulation of MYC and BFL-1 further overcomes resistance to ABT-199 both in vitro and in vivo, engaging synergistic caspase-mediated apoptosis in DHL cultures and tumor xenografts. Together, these findings highlight the relevance of BFL-1 in DH lymphoma-associated drug resistance and support the combined use of a BCL-2 antagonist and a BET inhibitor as a promising therapeutic strategy for patients with aggressive DHL.

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Acknowledgements

The authors thank Jocabed Roldan, Laura Jimenez, and Sandra Cabezas for expert technical assistance. This work was financially supported by Fondo de Investigación Sanitaria PI12/01847 and PI15/00102 (to G.R.), PI12/01536 (to A.L.-G.), European Regional Development Fund (ERDF) “Una manera de hacer Europa”, Redes Temáticas de Investigación Cooperativa de Cáncer from the Instituto de Salud Carlos III RD12/0036/0004 (to D.C.) and RD12/0036/0039 (to E.C.) and Generalitat de Catalunya 2014SGR346 (to D.C.) and 2014SGR795 (to E.C.). A.E.-A. was recipient of a predoctoral fellowship from Ministerio de Ciencia e Innovación (FPU). A.C.-J. holds a postdoctoral fellowship from The Agency for Management of University and Research (AGAUR, Beatriu de Pinós 2014 BP-B00177). This work was carried out at the Esther Koplowitz Center, Barcelona, under the CERCA Program (Generalitat de Catalunya).

Author contributions

A.E.-A. and J.G.V. designed study, performed experiments, analyzed data, and co‐wrote the manuscript. A.C.-J., D.G., and I.D. were in charge of and/or provided support to cell line transfection, western blot assay, flow cytometry analysis, and interpretation of the data. V.R. provided support in animal studies. I.S. supervised cell line authentication. E.C. and D.C. reviewed the manuscript. A.M. helped in designing immunohistochemical assays. G.Ry. provided essential primary samples. P.P.-G. helped in interpreting the results and reviewed the manuscript. A.L.-G. co-designed the study and reviewed the manuscript. G.Ro. conceived and designed the study, analyzed data, interpreted the results, and wrote the manuscript.

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Author notes

  1. A. Esteve-Arenys and J.G. Valero contributed equally to this work.

  2. A. Lopez-Guillermo and G. Roué contributed equally to this work.

Authors and Affiliations

  1. Aggressive B-cell Lymphoma Study Group, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain

    A. Esteve-Arenys, J. G. Valero, A. Chamorro-Jorganes, D. Gonzalez & G. Roué

  2. Division of Hematology and Oncology, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain

    A. Esteve-Arenys, J. G. Valero, A. Chamorro-Jorganes, D. Gonzalez, V. Rodriguez, I. Salaverria, E. Campo, D. Colomer, P. Pérez-Galán, A. Lopez-Guillermo & G. Roué

  3. Department of Hematology, Hospital Clinic, Barcelona, Spain

    I. Dlouhy & A. Lopez-Guillermo

  4. Hematopathology Unit, Department of Pathology, Hospital Clinic, Barcelona, Spain

    E. Campo, D. Colomer & A. Martinez

  5. Department of Pathology, The Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

    G. Rymkiewicz

  6. Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

    G. Roué

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  1. A. Esteve-Arenys
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Esteve-Arenys, A., Valero, J.G., Chamorro-Jorganes, A. et al. The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma. Oncogene 37, 1830–1844 (2018). https://doi.org/10.1038/s41388-017-0111-1

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