Journal
CELL REPORTS
Volume 17, Issue 9, Pages 2367-2381Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.10.077
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Funding
- NIH [R01 CA090687]
- Dana-Farber Specialized Program of Research Excellence (SPORE) in Breast Cancer [P50 CA168504]
- Susan G. Komen Investigator Initiated Research grant [IIR12223953]
- Dana-Farber Claudia Adams Barr Award
- National Health and Medical Research Council of Australia Fellowship
- Instituto de Salud Carlos III grant [PI12/02606]
- Asociacion Espanola Contra el Cancer
- Deutsche Forschungsgemeinschaft grant [GE 976/9-1]
- Merck Co.
- AstraZeneca
- Research Supplement to Promote Diversity in Health-Related Research [R01 CA090687]
- SPORE Diversity Career Development Award [P50 CA168504]
- National Breast Cancer Foundation [PRAC-14-002] Funding Source: researchfish
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Although poly (ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance. Additionally, we show that de novo resistance to PARP inhibition in BRCA1-mutated cell lines and a PDX derived from a PARP-inhibitor-naive BRCA1 carrier is mediated by residual HR and is reversed by CDK12 inhibition. Finally, dinaciclib augments the degree of response in a PARP-inhibitor-sensitive model, converting tumor growth inhibition to durable regression. These results highlight the significance of HR disruption as a therapeutic strategy and support the broad use of combined CDK12 and PARP inhibition in TNBC.
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