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Lymphoma

Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma

Leukemia volume 28, pages 2049–2059 (2014)Cite this article

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Abstract

Bortezomib therapy has shown promising clinical activity in mantle cell lymphoma (MCL), but the development of resistance to proteasome inhibition may limit its efficacy. To unravel the factors involved in the acquisition of bortezomib resistance in vivo, immunodeficient mice were engrafted with a set of MCL cell lines with different levels of sensitivity to the drug, followed by gene expression profiling of the tumors and functional validation of the identified gene signatures. We observed an increased tumorigenicity of bortezomib-resistant MCL cells in vivo, which was associated with plasmacytic differentiation features, like interferon regulatory factor 4 (IRF4) and Blimp-1 upregulation. Lenalidomide was particularly active in this subgroup of tumors, targeting IRF4 expression and plasmacytic differentiation program, thus overcoming bortezomib resistance. Moreover, repression of the IRF4 target gene MYC in bortezomib-resistant cells by gene knockdown or treatment with CPI203, a BET (bromodomain and extra terminal) bromodomain inhibitor, synergistically induced cell death when combined with lenalidomide. In mice, addition of CPI203 to lenalidomide therapy further decreased tumor burden, involving simultaneous MYC and IRF4 downregulation and apoptosis induction. Together, these results suggest that exacerbated IRF4/MYC signaling is associated to bortezomib resistance in MCL in vivo and warrant clinical evaluation of lenalidomide plus BET inhibitor combination in MCL cases refractory to proteasome inhibition.

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Acknowledgements

Bortezomib, lenalidomide and CPI203 were kindly provided by Millenium-Takeda Oncology, Celgene Corporation and Constellation Pharmaceuticals, respectively. This work was supported by grants from Fondo de Investigación Sanitaria (PI09/0060 and PI12/01847) (to G Roué), Ministerio de Economía y Competitividad (SAF 09/9503 and SAF 12/31242 to D Colomer; and SAF 11/29326 to P Pérez-Galán), Redes Temáticas de Investigación Cooperativa de Cáncer from the Instituto de Salud Carlos III (ISCIII) (RD2006/20/014 and RD12/0036/0004) and Generalitat de Catalunya 2009SGR967 (to D Colomer), European Regional Development Fund (ERDF) ‘Una manera de hacer Europa’. A Moros and A Montraveta were recipients of pre-doctoral fellowships from IDIBAPS and Ministerio de Ciencia e Innovación (FPI), respectively. A Martínez was supported by Instituto de Salud Carlos III, Fondo de Investigación Sanitaria and FEDER PI11/00907.

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Authors and Affiliations

  1. Hemato-Oncology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    A Moros, V Rodríguez, I Saborit-Villarroya, A Montraveta, P Balsas, E Campo, P Pérez-Galán, D Colomer & G Roué

  2. Department of Pharmacology, Constellation Pharmaceuticals, Inc., Cambridge, MA, USA

    P Sandy & E Normant

  3. Department of Pathology, Hematopathology Unit, Hospital Clínic, Barcelona, Spain

    A Martínez, E Campo & D Colomer

  4. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    A Wiestner

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Correspondence to G Roué.

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P Sandy and E Normant are employees with stock ownership in Constellation Pharmaceuticals, Inc. The remaining authors declare no conflict of interest.

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Moros, A., Rodríguez, V., Saborit-Villarroya, I. et al. Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma. Leukemia 28, 2049–2059 (2014). https://doi.org/10.1038/leu.2014.106

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