CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer
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.
|Authors||Johnson, S. F.; Cruz, C.; Greifenberg, A. K.; Dust, S.; Stover, D. G.; Chi, D.; Primack, B.; Cao, S.; Bernhardy, A. J.; Coulson, R.; Lazaro, J. B.; Kochupurakkal, B.; Sun, H.; Unitt, C.; Moreau, L. A.; Sarosiek, K. A.; Scaltriti, M.; Juric, D.; Baselga, J.; Richardson, A. L.; Rodig, S. J.; D'Andrea, A. D.; Balmana, J.; Johnson, N.; Geyer, M.; Serra, V.; Lim, E.; Shapiro, G. I.;|
|Publisher Name||Cell Reports|
|Published Date||2016-11-01 00:00:00|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/27880910|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13655|