CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer Journal Article
| 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.; Balmaña, J.; Johnson, N.; Geyer, M.; Serra, V.; Lim, E.; Shapiro, G. I. |
| Article Title: | CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer |
| 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. © 2016 The Author(s) |
| Keywords: | triple-negative breast cancer; cdk inhibitor; parp inhibitor; homologous recombination repair; cdk12; brca-associated breast cancer; dinaciclib |
| Journal Title: | Cell Reports |
| Volume: | 17 |
| Issue: | 9 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2016-11-22 |
| Start Page: | 2367 |
| End Page: | 2381 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2016.10.077 |
| PROVIDER: | scopus |
| PMCID: | PMC5176643 |
| PUBMED: | 27880910 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 January 2017 -- Source: Scopus |
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