BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články
PubMed
29025359
DOI
10.1177/1010428317727479
Knihovny.cz E-zdroje
- Klíčová slova
- BRCA1, CDK12, CHK1 inhibitor, DNA damage response, transcription,
- MeSH
- checkpoint kinasa 1 genetika MeSH
- chemorezistence genetika MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory genetika MeSH
- HCT116 buňky MeSH
- kolorektální nádory farmakoterapie genetika patologie MeSH
- lidé MeSH
- myši MeSH
- poly(ADP-ribosa)polymerasa 1 genetika MeSH
- poškození DNA účinky léků MeSH
- protein BRCA1 antagonisté a inhibitory genetika MeSH
- pyrazoly aplikace a dávkování MeSH
- pyrimidiny aplikace a dávkování MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- umlčování genů MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- CDK12 protein, human MeSH Prohlížeč
- checkpoint kinasa 1 MeSH
- CHEK1 protein, human MeSH Prohlížeč
- cyklin-dependentní kinasy MeSH
- MK-8776 MeSH Prohlížeč
- PARP1 protein, human MeSH Prohlížeč
- poly(ADP-ribosa)polymerasa 1 MeSH
- protein BRCA1 MeSH
- pyrazoly MeSH
- pyrimidiny 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
Citace poskytuje Crossref.org
