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Johnson SF , Cruz C , Greifenberg AK , Dust S , Stover DG , Chi D , Primack B , Cao S , Bernhardy AJ , Coulson R , Lazaro JB , Kochupurakkal B , Sun H , Unitt C , Moreau LA , Sarosiek KA , Scaltriti M , Juric D , Baselga J , Richardson AL , Rodig SJ , D'Andrea AD , Balmana J , Johnson N , Geyer M , Serra V , Lim E , Shapiro GI
CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer
Cell Rep. 2016 Nov 22;17(9) :2367-2381
PMID: 27880910    PMCID: PMC5176643    URL: https://www.ncbi.nlm.nih.gov/pubmed/27880910
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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.
Notes
2211-1247 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 Journal Article United States Cell Rep. 2016 Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077.