Abstract
Multiple myeloma (MM) is a hematological disease marked by abnormal growth of B cells in bone marrow. Inherent chromosomal instability and DNA damage are major hallmarks of MM, which implicates an aberrant DNA repair mechanism. Studies have implicated a role for CDK12 in the control of expression of DNA damage response genes. In this study, we examined the effect of a small molecule inhibitor of CDK12–THZ531 on MM cells. Treatment of MM cells with THZ531 led to heightened cell death accompanied by an extensive effect on gene expression changes. In particular, we observed downregulation of genes involved in DNA repair pathways. With this insight, we extended our study to identify synthetic lethal mechanisms that could be exploited for the treatment of MM cells. Combination of THZ531 with either DNA-PK inhibitor (KU-0060648) or PARP inhibitor (Olaparib) led to synergistic cell death. In addition, combination treatment of THZ531 with Olaparib significantly reduced tumor burden in animal models. Our findings suggest that using a CDK12 inhibitor in combination with other DNA repair inhibitors may establish an effective therapeutic regimen to benefit myeloma patients.
Highlights
Multiple myeloma (MM) is a clonal B-cell malignancy that classically displays proliferation of plasma cells in the bone marrow accompanied by extensive chromosomal instability in those cells
Intrinsic DNA damage and chromosomal instability are hallmarks of MM resulting in perpetual accumulation of genetic alterations that lead to progression of the disease
Wildtype CDK12 has vulnerability in EWS/FLI-positive Ewing sarcoma cells treated with THZ531, leading to downregulation of HRR genes [28]
Summary
Multiple myeloma (MM) is a clonal B-cell malignancy that classically displays proliferation of plasma cells in the bone marrow accompanied by extensive chromosomal instability in those cells. The molecular basis of genomic stability is not fully understood, recently, it has been reported that the DNA damage response (DDR) may influence genomic changes in MM [1]. Defective DNA repair function provides an alternative explanation for aneuploidy and chromosomal rearrangements evidenced in MM cells [2]. These events further contribute to drug resistance in MM cells and defective. DNA repair mechanisms have been implicated in the pathogenesis of MM [3,4,5]. DNA damaging chemotherapy has been the longstanding treatment strategy for cancer; it is accompanied by toxic side-effects and development of drug resistance over time. A new in line approach, synthetic lethality (SL), holds great promise in cancer therapeutics
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