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Yoichi Imai
The Institute of Medical Science, The University of Tokyo 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Corresponding Author
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Background: Multiple myeloma (MM) patients may undergo relapse and experience resistance to existing therapies. Cereblon (CRBN) is key mediator of the bioactivities of immunomodulatory drugs (IMiDs), including lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and 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 treatment of relapsed/refractory MM patients.
Methods: We established lenalidomide-resistant cells by knocking down or knocking out CRBN 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 placed on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells.
Results: HDAC inhibitor suppressed the growth of drug-resistant MM cell lines, and enhanced 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 glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Meanwhile, 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. Moreover, the dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects for MM cells, including for multi-drug-resistant lines and primary cells including lenalidomide-resistant patients.
Conclusions: Combined HDAC and Akt inhibition represents a promising approach for the treatment of relapsed/refractory MM.
Keywords
Multiple myeloma, Cereblon, Drug-resistance, HDAC inhibitor, Akt inhibitor, dual HDAC and PI3K inhibitor, Natural killer group 2D ligands, c-Myc, Monoclonal antibody, Antibody-dependent cellular cytotoxicity
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View the published article at Journal of Experimental & Clinical Cancer Research.
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Posted 15 Dec, 2020
No community comments so far
Editorial decision: Major revision
On 17 Dec, 2020
Review #1 received
Received 11 Dec, 2020
Review #2 received
Received 11 Dec, 2020
Reviewer #3 agreed
On 09 Dec, 2020
Reviewer #2 agreed
On 06 Dec, 2020
Editor assigned
On 06 Dec, 2020
Reviewers invited
Invitations sent on 06 Dec, 2020
Reviewer #1 agreed
On 06 Dec, 2020
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On 06 Dec, 2020
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On 06 Dec, 2020
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Subject Areas
Cancer Biology
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A new preprint design is coming!
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See the published version of this preprint at Journal of Experimental & Clinical Cancer Research.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Yoichi Imai
The Institute of Medical Science, The University of Tokyo 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Journal of Experimental & Clinical Cancer Research.
Version 1
Posted 15 Dec, 2020
No community comments so far
Editorial decision: Major revision
On 17 Dec, 2020
Review #1 received
Received 11 Dec, 2020
Review #2 received
Received 11 Dec, 2020
Reviewer #3 agreed
On 09 Dec, 2020
Reviewer #2 agreed
On 06 Dec, 2020
Editor assigned
On 06 Dec, 2020
Reviewers invited
Invitations sent on 06 Dec, 2020
Reviewer #1 agreed
On 06 Dec, 2020
Submission checks complete
On 06 Dec, 2020
Editor invited
On 06 Dec, 2020
First submitted
On 05 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Journal of Experimental & Clinical Cancer Research.
Background: Multiple myeloma (MM) patients may undergo relapse and experience resistance to existing therapies. Cereblon (CRBN) is key mediator of the bioactivities of immunomodulatory drugs (IMiDs), including lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and 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 treatment of relapsed/refractory MM patients.
Methods: We established lenalidomide-resistant cells by knocking down or knocking out CRBN 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 placed on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells.
Results: HDAC inhibitor suppressed the growth of drug-resistant MM cell lines, and enhanced 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 glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Meanwhile, 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. Moreover, the dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects for MM cells, including for multi-drug-resistant lines and primary cells including lenalidomide-resistant patients.
Conclusions: Combined HDAC and Akt inhibition represents a promising approach for the treatment of relapsed/refractory MM.
Figure 1
Figure 1
Figure 2
Figure 2
Figure 3
Figure 3
Figure 4
Figure 4
Figure 5
Figure 5
Figure 6
Figure 6
Figure 7
Figure 7
Figure 8
Figure 8
This is a list of supplementary files associated with this preprint. Click to download.
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