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https://doi.org/10.3390/ijms23031207
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dc.title | THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors | |
dc.contributor.author | Shyamsunder, Pavithra | |
dc.contributor.author | Sridharan, Shree Pooja | |
dc.contributor.author | Madan, Vikas | |
dc.contributor.author | Dakle, Pushkar | |
dc.contributor.author | Zeya, Cao | |
dc.contributor.author | Kanojia, Deepika | |
dc.contributor.author | Chng, Wee-Joo | |
dc.contributor.author | Ong, S Tiong | |
dc.contributor.author | Koeffler, H Phillip | |
dc.date.accessioned | 2022-07-21T04:34:11Z | |
dc.date.available | 2022-07-21T04:34:11Z | |
dc.date.issued | 2022-02-01 | |
dc.identifier.citation | Shyamsunder, Pavithra, Sridharan, Shree Pooja, Madan, Vikas, Dakle, Pushkar, Zeya, Cao, Kanojia, Deepika, Chng, Wee-Joo, Ong, S Tiong, Koeffler, H Phillip (2022-02-01). 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). ScholarBank@NUS Repository. https://doi.org/10.3390/ijms23031207 | |
dc.identifier.issn | 16616596 | |
dc.identifier.issn | 14220067 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/228992 | |
dc.description.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 in-sight, 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. | |
dc.language.iso | en | |
dc.publisher | MDPI | |
dc.source | Elements | |
dc.subject | Science & Technology | |
dc.subject | Life Sciences & Biomedicine | |
dc.subject | Physical Sciences | |
dc.subject | Biochemistry & Molecular Biology | |
dc.subject | Chemistry, Multidisciplinary | |
dc.subject | Chemistry | |
dc.subject | DNA repair | |
dc.subject | BRCAness | |
dc.subject | THZ531 | |
dc.subject | Olaparib | |
dc.subject | DEPENDENT KINASE INHIBITOR | |
dc.subject | STRAND BREAK REPAIR | |
dc.subject | HOMOLOGOUS RECOMBINATION | |
dc.subject | GENOMIC STABILITY | |
dc.subject | CDK12 INHIBITION | |
dc.subject | DAMAGE RESPONSE | |
dc.subject | PROTEIN-KINASE | |
dc.subject | WILD-TYPE | |
dc.subject | EXPRESSION | |
dc.subject | RESISTANCE | |
dc.type | Article | |
dc.date.updated | 2022-07-17T12:04:08Z | |
dc.contributor.department | CANCER SCIENCE INSTITUTE OF SINGAPORE | |
dc.contributor.department | DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL) | |
dc.contributor.department | DEAN'S OFFICE (MEDICINE) | |
dc.contributor.department | DUKE-NUS MEDICAL SCHOOL | |
dc.description.doi | 10.3390/ijms23031207 | |
dc.description.sourcetitle | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | |
dc.description.volume | 23 | |
dc.description.issue | 3 | |
dc.published.state | Published | |
Appears in Collections: | Staff Publications Elements |
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