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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Multiple Myeloma | Research

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

Authors: Mitsuhito Hirano, Yoichi Imai, Yuta Kaito, Takahiko Murayama, Kota Sato, Tadao Ishida, Junichi Yamamoto, Takumi Ito, Muneyoshi Futami, Masaki Ri, Hiroshi Yasui, Tamami Denda, Yukihisa Tanaka, Yasunori Ota, Masanori Nojima, Yasuhiko Kamikubo, Noriko Gotoh, Shinsuke Iida, Hiroshi Handa, Arinobu Tojo

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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.

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Title: Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma
Authors: Mitsuhito Hirano
Yoichi Imai
Yuta Kaito
Takahiko Murayama
Kota Sato
Tadao Ishida
Junichi Yamamoto
Takumi Ito
Muneyoshi Futami
Masaki Ri
Hiroshi Yasui
Tamami Denda
Yukihisa Tanaka
Yasunori Ota
Masanori Nojima
Yasuhiko Kamikubo
Noriko Gotoh
Shinsuke Iida
Hiroshi Handa
Arinobu Tojo
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Multiple Myeloma
Daratumumab
Elotuzumab
Dexamethasone
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01909-7

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