Journal
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume 40, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13046-021-01909-7
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
Categories
Funding
- Okinaka Memorial Institute for Medical Research
- JSPS KAKENHI [17K09916, 20K08726]
- Janssen
- Celgene/Bristol-Myers Squibb
- Grants-in-Aid for Scientific Research [20K08726, 17K09916] Funding Source: KAKEN
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The study found that the combination of HDAC inhibitor and Akt inhibitor holds promise for the treatment of relapsed/refractory MM, as HDAC inhibitors suppressed drug-resistant MM cell growth and enhanced antibody-dependent cellular cytotoxicity, while also downregulating c-Myc through GSK-3 phosphorylation blockage.
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.
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