MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance.
Clin Cancer Res
; 30(14): 3023-3035, 2024 Jul 15.
Article
in En
| MEDLINE
| ID: mdl-38723281
ABSTRACT
PURPOSE:
Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are a cornerstone of multiple myeloma (MM) therapies, yet the disease inevitably becomes refractory. IMiDs exert cytotoxicity by inducing cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, resulting in downregulation of the oncogenic transcription factors IRF4 and MYC. To date, clinical IMiD resistance independent of cereblon or IKZF1/3 has not been well explored. Here, we investigated the roles of IRF4 and MYC in this context. EXPERIMENTALDESIGN:
Using bone marrow aspirates from patients with IMiD-naïve or refractory MM, we examined IKZF1/3 protein levels and IRF4/MYC gene expression following ex vivo pomalidomide treatment via flow cytometry and qPCR. We also assessed exvivo sensitivity to the MYC inhibitor MYCi975 using flow cytometry.RESULTS:
We discovered that although pomalidomide frequently led to IKZF1/3 degradation in MM cells, it did not affect MYC gene expression in most IMiD-refractory samples. We subsequently demonstrated that MYCi975 exerted strong anti-MM effects in both IMiD-naïve and -refractory samples. Unexpectedly, we identified a cluster of differentiation 8+ (CD8+ T) cells from patients with MM as crucial effectors of MYCi975-induced cytotoxicity in primary MM samples, and we discovered that MYCi975 enhanced the cytotoxic functions of memory CD8+ T cells. We lastly observed synergy between MYCi975 and pomalidomide in IMiD-refractory samples, suggesting that restoring MYC downregulation can re-sensitize refractory MM to IMiDs.CONCLUSIONS:
Our study supports the concept that MYC represents an Achilles' heel in MM across disease states and that MYCi975 may be a promising therapeutic for patients with MM, particularly in combination with IMiDs.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thalidomide
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Proto-Oncogene Proteins c-myc
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CD8-Positive T-Lymphocytes
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Drug Resistance, Neoplasm
/
Interferon Regulatory Factors
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Ikaros Transcription Factor
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Immunomodulating Agents
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Multiple Myeloma
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
Clin Cancer Res
Journal subject:
NEOPLASIAS
Year:
2024
Document type:
Article
Country of publication: