CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in 
BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer

Johnson, Shawn F.; Cruz, Cristina; Greifenberg, Ann Katrin; Dust, Sofia; Stover, Daniel G.; Chi, David; Primack, Benjamin; Cao, Shiliang; Bernhardy, Andrea J.; Coulson, Rhiannon; Lazaro, Jean-Bernard; Kochupurakkal, Bose; Sun, Heather; Unitt, Christine; Moreau, Lisa A.; Sarosiek, Kristopher A.; Scaltriti, Maurizio; Juric, Dejan; Baselga, Jose; Richardson, Andrea L.; Rodig, Scott J.; D'Andrea, Alan D.; Balmana, Judith; Johnson, Neil; Geyer, Matthias; Serra, Violeta; Lim, Elgene; Shapiro, Geoffrey I.

doi:10.1016/j.celrep.2016.10.077

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CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer

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Greifenberg, Ann Katrin
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;

Dust, Sofia
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Geyer, Matthias
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Citation

Johnson, S. F., Cruz, C., Greifenberg, A. K., Dust, S., Stover, D. G., Chi, D., et al. (2016). CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Reports, 17(9), 2367-2381. doi:10.1016/j.celrep.2016.10.077.

Cite as: https://hdl.handle.net/21.11116/0000-0006-F09B-C

Abstract

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.