Genome-wide Profiling of Genetic Synthetic Lethality Identifies CDK12 as a Novel Determinant of PARP1/2 Inhibitor Sensitivity

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dc.contributor.authorBajrami, Ilirjana
dc.contributor.authorFrankum, Jessica R.
dc.contributor.authorKonde, Asha
dc.contributor.authorSims, David
dc.contributor.authorKozarewa, Iwanka
dc.contributor.authorLord, Christopher J.
dc.date.accessioned2023-04-17T17:15:36Z
dc.date.available2023-04-17T17:15:36Z
dc.date.issued2014
dc.description.abstractSmall-molecule inhibitors of PARP1/2, such as olaparib, have been proposed to serve as a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials, PARP1/2 inhibitors elicit sustained antitumor responses in patients with germline BRCA gene mutations. In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51, and Fanconi's anemia susceptibility genes. In addition, the set included genes implicated in established networks of DNA repair, DNA cohesion, and chromatin remodeling, none of which were known previously to confer sensitivity to PARP1/2 inhibition. Notably, integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. As one of only nine genes known to be significantly mutated in HGS-OVCa, CDK12 has properties that should confirm interest in its use as a biomarker, particularly in ongoing clinical trials of PARP1/2 inhibitors and other agents that trigger replication fork arrest. Cancer Res; 74(1); 287–97. ©2013 AACR.en_US
dc.identifier.citationBajrami, I., Frankum, J. R., Konde, A., Miller, R. E., Rehman, F. L., Brough, R., ... & Ashworth, A. (2014). Genome-wide Profiling of Genetic Synthetic Lethality Identifies CDK12 as a Novel Determinant of PARP1/2 Inhibitor SensitivityCDK12 and PARP Inhibitor Sensitivity. Cancer research, 74(1), 287-297.https://doi.org/10.1158/0008-5472.CAN-13-2541en_US
dc.identifier.issn1538-7445
dc.identifier.urihttps://nru.uncst.go.ug/handle/123456789/8489
dc.language.isoenen_US
dc.publisherCancer researchen_US
dc.subjectInhibitor Sensitivityen_US
dc.subjectNovel Determinanten_US
dc.subjectGenome-wide Profilingen_US
dc.titleGenome-wide Profiling of Genetic Synthetic Lethality Identifies CDK12 as a Novel Determinant of PARP1/2 Inhibitor Sensitivityen_US
dc.typeArticleen_US
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