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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.

journal_name

Cell Rep

journal_title

Cell reports

authors

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

doi

10.1016/j.celrep.2016.10.077

subject

Has Abstract

pub_date

2016-11-22 00:00:00

pages

2367-2381

issue

9

issn

2211-1247

pii

S2211-1247(16)31512-1

journal_volume

17

pub_type

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