Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma.
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.
Hemato-Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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Moros
Hemato-Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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Rodríguez
Hemato-Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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I
Saborit-Villarroya
Hemato-Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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Montraveta
Hemato-Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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Balsas
Department of Pharmacology, Constellation Pharmaceuticals, Inc., Cambridge, MA, USA.
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Sandy
Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain.
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Martínez
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
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Wiestner
Department of Pharmacology, Constellation Pharmaceuticals, Inc., Cambridge, MA, USA.
E
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Normant
1] Hemato-Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain [2] Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain.
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Campo
Hemato-Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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Pérez-Galán
1] Hemato-Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain [2] Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain.
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Colomer
Hemato-Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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Roué
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D020869:Gene Expression Profiling; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D000077269:Lenalidomide; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D061988:Proteasome Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000099218:Interferon Regulatory Factor-4
D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D050835:Interferon Regulatory Factors; D000077269:Lenalidomide; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D013792:Thalidomide; D000099218:Interferon Regulatory Factor-4