Mitsuhito Hirano1, Yoichi Imai2, Yuta Kaito1, Takahiko Murayama3, Kota Sato4, Tadao Ishida4, Junichi Yamamoto5,6, Takumi Ito6, Muneyoshi Futami1,7, Masaki Ri8, Hiroshi Yasui7,9, Tamami Denda10, Yukihisa Tanaka10, Yasunori Ota10, Masanori Nojima11, Yasuhiko Kamikubo12, Noriko Gotoh3, Shinsuke Iida8, Hiroshi Handa6, Arinobu Tojo1,7. 1. Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 2. Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. imaiyo-tky@umin.ac.jp. 3. Division of Cancer Cell Biology, Cancer Research Institute of Kanazawa University, Kanazawa, Japan. 4. Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan. 5. School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan. 6. Department of Chemical Biology, Tokyo Medical University, Tokyo, Japan. 7. Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 8. Department of Hematology & Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 9. Project Division of Fundamental Study on Cutting Edge of Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 10. Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 11. Center for Translational Research/Division of Advanced Medicine Promotion The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 12. Laboratory of Oncology and Strategic Innovation, Laboratory Science, Graduate School of Medicine Kyoto University, Kyoto, Japan.
Abstract
BACKGROUND: Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and is considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in relapsed/refractory MM patients. METHODS: We established lenalidomide-resistant cells by knocking down CRBN with RNAi-mediated downregulation or knocking out CRBN using CRISPR-Cas9 in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells. RESULTS: The HDAC inhibitor suppressed the growth of drug-resistant MM cell lines and enhanced the antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Moreover, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc-suppressive effects. The dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects in MM cells, including multi-drug-resistant lines and primary cells from lenalidomide-resistant patients. CONCLUSIONS: The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.
BACKGROUND:Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and is considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in relapsed/refractory MM patients. METHODS: We established lenalidomide-resistant cells by knocking down CRBN with RNAi-mediated downregulation or knocking out CRBN using CRISPR-Cas9 in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells. RESULTS: The HDAC inhibitor suppressed the growth of drug-resistant MM cell lines and enhanced the antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Moreover, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc-suppressive effects. The dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects in MM cells, including multi-drug-resistant lines and primary cells from lenalidomide-resistant patients. CONCLUSIONS: The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.
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