Home Blog of Signal Transduction DNA Damage/DNA Repair DNA-PK THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors

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THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors

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.

 

Comments:

Your study focused on investigating the effect of a small molecule inhibitor of CDK12, called THZ531, on multiple myeloma (MM) cells. The results showed that treatment with THZ531 resulted in increased cell death and significant changes in gene expression. Specifically, genes involved in DNA repair pathways were downregulated.

Building on these findings, you further explored potential synthetic lethal mechanisms that could be targeted for the treatment of MM cells. Combining THZ531 with either a DNA-PK inhibitor (KU-0060648) or a PARP inhibitor (Olaparib) resulted in synergistic cell death. Furthermore, when THZ531 was combined with Olaparib, there was a significant reduction in tumor burden in animal models.

Based on these observations, your study suggests that utilizing a CDK12 inhibitor in combination with other DNA repair inhibitors could establish an effective therapeutic strategy for the benefit of multiple myeloma patients. The combination of THZ531 with Olaparib, in particular, demonstrated promising results in reducing tumor burden.

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S8045 KU-0060648 KU-0060648 is a dual inhibitor of DNA-PK and PI3Kα, PI3Kβ, PI3Kδ with IC50 of 8.6 nM and 4 nM, 0.5 nM, 0.1 nM respectively, less inhibition of PI3Kγ with IC50 of 0.59 μM.

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DNA-PK PI3K