BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

Tumour Biol. 2017 Oct;39(10):1010428317727479. doi: 10.1177/1010428317727479.

Abstract

A broad spectrum of tumors develop resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly(ADP-ribose) polymerase 1/2 proteins and DNA damage response genes, including BRCA1, a factor involved in homologous recombination-mediated DNA repair, and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. CHK1 inhibitors have been shown to enhance the anti-cancer effect of DNA-damaging compounds. Since loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival. The silencing of BRCA1 or CDK12 sensitized tumor cells to CHK1 inhibitors in vitro and in vivo. BRCA1 downregulation combined with CHK1 inhibition induced excessive amounts of DNA damage, resulting in an inability to complete the S-phase. Therefore, we suggest CHK1 inhibition as a strategy for targeting BRCA1- or CDK12-deficient tumors.

Keywords: BRCA1; CDK12; CHK1 inhibitor; DNA damage response; transcription.

MeSH terms

  • Animals
  • BRCA1 Protein / antagonists & inhibitors
  • BRCA1 Protein / genetics*
  • Checkpoint Kinase 1 / genetics*
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / genetics*
  • DNA Damage / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Silencing
  • HCT116 Cells
  • Humans
  • Mice
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Pyrazoles / administration & dosage
  • Pyrimidines / administration & dosage
  • Xenograft Model Antitumor Assays

Substances

  • BRCA1 Protein
  • MK-8776
  • Pyrazoles
  • Pyrimidines
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • CDK12 protein, human
  • Cyclin-Dependent Kinases