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Article

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

by
Pavithra Shyamsunder
1,2,*,
Shree Pooja Sridharan
1,
Vikas Madan
1,
Pushkar Dakle
1,
Cao Zeya
1,
Deepika Kanojia
1,
Wee-Joo Chng
1,3,
S. Tiong Ong
2,4,5,6 and
H. Phillip Koeffler
1,3,7
1
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
2
Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
3
Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore 119074, Singapore
4
Department of Haematology, Singapore General Hospital, Singapore 169608, Singapore
5
Department of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore
6
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
7
Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA 90095, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(3), 1207; https://doi.org/10.3390/ijms23031207
Submission received: 15 December 2021 / Revised: 13 January 2022 / Accepted: 17 January 2022 / Published: 21 January 2022
(This article belongs to the Section Biochemistry)
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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.
Keywords: DNA repair; BRCAness; THZ531; Olaparib DNA repair; BRCAness; THZ531; Olaparib

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MDPI and ACS Style

Shyamsunder, P.; Sridharan, S.P.; Madan, V.; Dakle, P.; Zeya, C.; Kanojia, D.; Chng, W.-J.; Ong, S.T.; Koeffler, H.P. THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors. Int. J. Mol. Sci. 2022, 23, 1207. https://doi.org/10.3390/ijms23031207

AMA Style

Shyamsunder P, Sridharan SP, Madan V, Dakle P, Zeya C, Kanojia D, Chng W-J, Ong ST, Koeffler HP. THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors. International Journal of Molecular Sciences. 2022; 23(3):1207. https://doi.org/10.3390/ijms23031207

Chicago/Turabian Style

Shyamsunder, Pavithra, Shree Pooja Sridharan, Vikas Madan, Pushkar Dakle, Cao Zeya, Deepika Kanojia, Wee-Joo Chng, S. Tiong Ong, and H. Phillip Koeffler. 2022. "THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors" International Journal of Molecular Sciences 23, no. 3: 1207. https://doi.org/10.3390/ijms23031207

APA Style

Shyamsunder, P., Sridharan, S. P., Madan, V., Dakle, P., Zeya, C., Kanojia, D., Chng, W.-J., Ong, S. T., & Koeffler, H. P. (2022). THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors. International Journal of Molecular Sciences, 23(3), 1207. https://doi.org/10.3390/ijms23031207

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