Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma.

Angiogenesis Inhibitors / pharmacology Animals Female Histone Deacetylase Inhibitors / pharmacology Humans Immunotherapy / methods Male Mice Multiple Myeloma / drug therapy
Akt inhibitor Antibody-dependent cellular cytotoxicity C-Myc Cereblon Drug-resistance Dual HDAC and PI3K inhibitor HDAC inhibitor Monoclonal antibody Multiple myeloma Natural killer group 2D ligands

Journal

Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647

Informations de publication

Date de publication:
23 Mar 2021
Historique:
received: 06 12 2020
accepted: 14 03 2021
entrez: 24 3 2021
pubmed: 25 3 2021
medline: 3 11 2021
Statut: epublish

Résumé

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. 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. 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. The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.

Sections du résumé

BACKGROUND 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 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 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 CONCLUSIONS
The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.

Identifiants

DOI: 10.1186/s13046-021-01909-7 PMID: 33757580 PMC: PMC7989023
pubmed: 33757580
doi: 10.1186/s13046-021-01909-7
pii: 10.1186/s13046-021-01909-7
pmc: PMC7989023
doi:

Substances chimiques

Angiogenesis Inhibitors 0
Histone Deacetylase Inhibitors 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

110

Subventions

Organisme : Japan Society for the Promotion of Science
ID : 1 7 K 0 9 9 1 6
Organisme : Japan Society for the Promotion of Science
ID : 2 0 K 0 8 7 2 6

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Auteurs

Mitsuhito Hirano (M)

Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Yoichi Imai (Y)

Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. imaiyo-tky@umin.ac.jp.

Yuta Kaito (Y)

Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Takahiko Murayama (T)

Division of Cancer Cell Biology, Cancer Research Institute of Kanazawa University, Kanazawa, Japan.

Kota Sato (K)

Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.

Tadao Ishida (T)

Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.

Junichi Yamamoto (J)

School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan.
Department of Chemical Biology, Tokyo Medical University, Tokyo, Japan.

Takumi Ito (T)

Department of Chemical Biology, Tokyo Medical University, Tokyo, Japan.

Muneyoshi Futami (M)

Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Masaki Ri (M)

Department of Hematology & Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Hiroshi Yasui (H)

Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Project Division of Fundamental Study on Cutting Edge of Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Tamami Denda (T)

Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Yukihisa Tanaka (Y)

Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Yasunori Ota (Y)

Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Masanori Nojima (M)

Center for Translational Research/Division of Advanced Medicine Promotion The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Yasuhiko Kamikubo (Y)

Laboratory of Oncology and Strategic Innovation, Laboratory Science, Graduate School of Medicine Kyoto University, Kyoto, Japan.

Noriko Gotoh (N)

Division of Cancer Cell Biology, Cancer Research Institute of Kanazawa University, Kanazawa, Japan.

Shinsuke Iida (S)

Department of Hematology & Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Hiroshi Handa (H)

Department of Chemical Biology, Tokyo Medical University, Tokyo, Japan.

Arinobu Tojo (A)

Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Inhibiteurs de l'angiogenèse › Small-molecule HDAC and Akt inhibitors...
questionsmedicales.fr › Eucaryotes › Animaux › Small-molecule HDAC and Akt inhibitors...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de désacétylase d'histone › Small-molecule HDAC and Akt inhibitors...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Small-molecule HDAC and Akt inhibitors...
questionsmedicales.fr › Thérapeutique › Biothérapie › Immunothérapie › Small-molecule HDAC and Akt inhibitors...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Small-molecule HDAC and Akt inhibitors...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Paraprotéinémies › Myélome multiple › Small-molecule HDAC and Akt inhibitors...