Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 20, Pages 6195-6205Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-3788
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Funding
- NCI [CA205607, UH2TR001373]
- Leukemia and Lymphoma Society (LLS) [R6508-18]
- NIH-NCI Cancer Center [P30 CA016059]
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Purpose: The goal of this study was to characterize the activity of the covalent CDK7 inhibitor THZ1 in multiple myeloma models. Experimental Design: Multiple myeloma lines were exposed to varying THZ1 concentrations alone or with carfilzomib or ABT-199, after which apoptosis was monitored by flow cytometry, protein expression by Western blot analysis, mRNA by RT-PCR. Analogous studies were performed in cells ectopically expressing c-MYC, MCL-1, or BCL-XL, or CRISPER-Cas CDK7 sgRNA knockout. Primary multiple myeloma cells were exposed to THZ1 +/- carfilzomib or ABT-199. In vivo effects of THZ1 were examined in a systemic U266 xenograft model. Results: THZ1 markedly diminished multiple myeloma cell proliferation and survival despite bortezomib or stromal cell resistance in association with G(2)-M arrest, inactivation of CTD RNAPol II, dephosphorylation of CDKs 7 as well as 1, 2, and 9, and MCL-1, BCL-xL, and c-MYC mRNA or protein downregulation. Ectopic MCL-1, c-MYC, or BCL-X-L expression significantly protected cells from THZ1 lethality. Both THZ1 and CRISPR-Cas CDK7 knockout sharply diminished multiple myeloma cell proliferation and significantly increased carfilzomib and ABT-199 lethality. Parallel effects and interactions were observed in primary CD138(+) (N = 22) or primitive multiple myeloma cells (CD138(-)/CD19(+)/CD20(+)/CD27(+); N = 16). THZ1 administration [10 mg/kg i.p. twice daily (BID), 5 days/week] significantly improved survival in a systemic multiple myeloma xenograft model with minimal toxicity and induced similar events observed in vitro, for example, MCL-1 and c-MYC downregulation. Conclusions: THZ1 potently reduces multiple myeloma cell proliferation through transcriptional downregulation of MCL-1, BCL-X-L, and c-MYC in vitro and in vivo. It warrants further attention as a therapeutic agent inmultiplemyeloma.
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