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Cited by 25Multiple Myeloma Research and TreatmentsProtein Degradation and InhibitorsHistone Deacetylase Inhibitors Research

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

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Hirano, Mitsuhito, Imai, Yoichi, Kaito, Yuta, Murayama, Takahiko, Sato, Kota, Ishida, Tadao, Yamamoto, Junichi, Ito, Takumi +12 more·2021·Journal of Experimental & Clinical Cancer Research
DOI 10.1186/s13046-021-01909-7PMC PMC7989023

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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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  • Aberrant activation of these signaling pathways contributes to proliferation, survival, migration, and drug resistance of myeloma cells.

    “Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention.”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [37]

    The Background (page unavailable) says the PI3K/Akt pathway is aberrantly activated in multiple myeloma and links its downstream signaling to cell survival and lenalidomide resistance. It also links aberrant epigenetic changes to tumor proliferation, and the Conclusions describe HDAC and Akt inhibitors as promising treatments. Our copy does not link these pathways to myeloma-cell migration, so it does not support the full list of effects. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Targeting proteins that mediate these signaling pathways holds promise as a potential therapeutic approach for MM treatment.

    “Targeting proteins that mediate these signaling pathways holds promise as a potential therapeutic approach for MM treatment [32, 35–39].”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [37]

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Authors
Hirano, M., Imai, Y., Kaito, Y., Murayama, T., Sato, K., Ishida, T., Yamamoto, J., Ito, T., Futami, M., Ri, M., Yasui, H., Denda, T., Tanaka, Y., Ota, Y., Nojima, M., Kamikubo, Y., Gotoh, N., Iida, S., Handa, H., & Tojo, A.
Affiliations
  • Institute of Medical Science, The University of Tokyo (JP)
  • Cancer Research Institute of Kanazawa University (JP)
  • Japanese Red Cross Medical Center (JP)
  • Tokyo Institute of Technology (JP)
  • Tokyo Medical University (JP)
  • Nagoya City University (JP)
  • The University of Tokyo (JP)
  • Kyoto University (JP)
Corresponding author
Imai, Yoichi
ORCID
Venue
Journal of Experimental & Clinical Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2021-03-23
Volume
40
Issue
1
Pages
110-110
ISSN
  • 0392-9078 (ISSN-L)
  • 1756-9966
DOI
10.1186/s13046-021-01909-7
PMC
PMC7989023
OpenAlex
W3112350425
Cited by
25
References
8
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 4
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Janssen Pharmaceuticals
  • Bristol-Myers Squibb
  • Okinaka Memorial Institute for Medical Research
  • Japan Society for the Promotion of Science (1 7 K 0 9 9 1 6, 2 0 K 0 8 7 2 6)
  • Takeda Pharmaceutical Company
  • AbbVie
  • MSD K.K.
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Keywords
multiple myeloma, histone deacetylase inhibitors, AKT inhibitors, lenalidomide resistance, cereblon, immunomodulators, drug resistance, c-Myc, glycogen synthase kinase-3, NKG2D ligands, antibody-dependent cellular cytotoxicity, CUDC-907, PI3K inhibitors, relapsed/refractory multiple myeloma
MeSH terms
Animals, Female, Humans, Immunotherapy, Male, Multiple Myeloma, Angiogenesis Inhibitors, Mice, Histone Deacetylase Inhibitors

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