학술논문
CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCAWild-Type and Mutated Models of Triple-Negative Breast Cancer
Document Type
Article
Author
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, José; Richardson, Andrea L.; Rodig, Scott J.; D’Andrea, Alan D.; Balmaña, Judith; Johnson, Neil; Geyer, Matthias; Serra, Violeta; Lim, Elgene; Shapiro, Geoffrey I.
Source
Cell Reports; November 2016, Vol. 17 Issue: 9 p2367-2381, 15p
Subject
Language
ISSN
22111247
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 BRCA1carrier 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.