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. doi: 10.1016/j.celrep.2016.10.077.

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.

Keywords: BRCA-associated breast cancer; CDK inhibitor; CDK12; PARP inhibitor; dinaciclib; homologous recombination repair; triple-negative breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / chemistry
  • Cyclin-Dependent Kinases / metabolism
  • DNA Damage / genetics
  • DNA Repair / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockout Techniques
  • Homologous Recombination / drug effects
  • Humans
  • Mice
  • Mutation / genetics*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Pyridinium Compounds / pharmacology
  • RNA, Small Interfering / metabolism
  • Transcription, Genetic / drug effects
  • Triple Negative Breast Neoplasms / enzymology*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / pathology*
  • Xenograft Model Antitumor Assays

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Bridged Bicyclo Compounds, Heterocyclic
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protein Kinase Inhibitors
  • Pyridinium Compounds
  • RNA, Small Interfering
  • dinaciclib
  • CDK12 protein, human
  • Cyclin-Dependent Kinases