[PDF][PDF] CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer

SF Johnson, C Cruz, AK Greifenberg, S Dust… - Cell reports, 2016 - cell.com
SF Johnson, C Cruz, AK Greifenberg, S Dust, DG Stover, D Chi, B Primack, S Cao
Cell reports, 2016cell.com
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 …
Summary
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.
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