Evidence map›Paper›PMID 33757580›Full record

ArticleJournal of experimental & clinical cancer research : CR2021

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

Mitsuhito Hirano, Yoichi Imai, Yuta Kaito, Takahiko Murayama, Kota Sato, Tadao Ishida, Junichi Yamamoto, Takumi Ito, Muneyoshi Futami, Masaki Ri and 10 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed
2.9field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

22 citing papers in PubMed, 24 citations in OpenAlex.

  1. Targeting MYC-Driven Cancers: From Oncogenic Addiction to Therapeutic Vulnerability.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026
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  15. Panobinostat enhances NK cell cytotoxicity in soft tissue sarcoma.Clinical and experimental immunology · 2022
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 8 institutions in 1 country.

Mitsuhito HiranoDivision of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yoichi ImaiDepartment of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. imaiyo-tky@umin.ac.jp.
Yuta KaitoDivision of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Takahiko MurayamaDivision of Cancer Cell Biology, Cancer Research Institute of Kanazawa University, Kanazawa, Japan.
Kota SatoDepartment of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.
Tadao IshidaDepartment of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.
Junichi YamamotoSchool of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan.
Takumi ItoDepartment of Chemical Biology, Tokyo Medical University, Tokyo, Japan.
Muneyoshi FutamiDivision of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Masaki RiDepartment of Hematology & Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Hiroshi YasuiDepartment of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Tamami DendaDepartment of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yukihisa TanakaDepartment of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yasunori OtaDepartment of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Masanori NojimaCenter for Translational Research/Division of Advanced Medicine Promotion The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yasuhiko KamikuboLaboratory of Oncology and Strategic Innovation, Laboratory Science, Graduate School of Medicine Kyoto University, Kyoto, Japan.
Noriko GotohDivision of Cancer Cell Biology, Cancer Research Institute of Kanazawa University, Kanazawa, Japan.
Shinsuke IidaDepartment of Hematology & Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Hiroshi HandaDepartment of Chemical Biology, Tokyo Medical University, Tokyo, Japan.
Arinobu TojoDivision of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
University of Tokyo Hospital · JPThe University of Tokyo · JPJapanese Red Cross Medical Center · JPKanazawa University · JPNagoya City University · JPTokyo Medical University · JPKyoto University · JPTokyo Institute of Technology · JP

Funding

Japan Society for the Promotion of Science 1 7 K 0 9 9 1 6Japan Society for the Promotion of Science 2 0 K 0 8 7 2 6
6 · The paper itself

Abstract

backgroundMultiple 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.

methodsWe 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.

resultsThe 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.

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

Indexed as

Angiogenesis InhibitorsAnimalsFemaleHistone Deacetylase InhibitorsHumansImmunotherapyMaleMiceMultiple MyelomaAngiogenesis InhibitorsHistone Deacetylase InhibitorsAkt inhibitorAntibody-dependent cellular cytotoxicityCereblonC-MycDrug-resistanceDual HDAC and PI3K inhibitorHDAC inhibitorMonoclonal antibodyMultiple myelomaNatural killer group 2D ligands

Identifiers

PMID33757580
PMCPMC7989023
OpenAlexW3112350425

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.