BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors
Language English Country United States Media print
Document type Journal Article
- Keywords
- BRCA1, CDK12, CHK1 inhibitor, DNA damage response, transcription,
- MeSH
- Checkpoint Kinase 1 genetics MeSH
- Drug Resistance, Neoplasm genetics MeSH
- Cyclin-Dependent Kinases antagonists & inhibitors genetics MeSH
- HCT116 Cells MeSH
- Colorectal Neoplasms drug therapy genetics pathology MeSH
- Humans MeSH
- Mice MeSH
- Poly (ADP-Ribose) Polymerase-1 genetics MeSH
- DNA Damage drug effects MeSH
- BRCA1 Protein antagonists & inhibitors genetics MeSH
- Pyrazoles administration & dosage MeSH
- Pyrimidines administration & dosage MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- Gene Silencing MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- CDK12 protein, human MeSH Browser
- Checkpoint Kinase 1 MeSH
- CHEK1 protein, human MeSH Browser
- Cyclin-Dependent Kinases MeSH
- MK-8776 MeSH Browser
- PARP1 protein, human MeSH Browser
- Poly (ADP-Ribose) Polymerase-1 MeSH
- BRCA1 Protein MeSH
- Pyrazoles MeSH
- Pyrimidines MeSH
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.
Department of Chemistry and Toxicology Veterinary Research Institute Brno Czech Republic
Department of Chemistry CZ Openscreen Faculty of Science Masaryk University Brno Czech Republic
Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic
Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic
Institute of Biophysics of the Czech Academy of Sciences Brno Czech Republic
International Clinical Research Center St Anne's University Hospital Brno Czech Republic
References provided by Crossref.org
CDK12: cellular functions and therapeutic potential of versatile player in cancer
CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes
