BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

• Published in: Tumor biology 2017-10, Vol.39 (10), p.1010428317727479-1010428317727479
• Main Authors: Paculová, Hana, Kramara, Juraj, Šimečková, Šárka, Fedr, Radek, Souček, Karel, Hylse, Ondřej, Paruch, Kamil, Svoboda, Marek, Mistrík, Martin, Kohoutek, Jiří
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Animals; BRCA1 protein; BRCA1 Protein - antagonists & inhibitors; BRCA1 Protein - genetics; Breast cancer; Cancer; Cancer therapies; Checkpoint Kinase 1 - genetics; Chemotherapy; CHK1 protein; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - genetics; DNA damage; DNA Damage - drug effects; DNA repair; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing; HCT116 Cells; Homologous recombination; Homology; Humans; Inhibition; Inhibitors; Kinases; Lethality; Mice; Ovarian cancer; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Proteins; Pyrazoles - administration & dosage; Pyrimidines - administration & dosage; Ribose; Transcription; Tumor cells; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1177/1010428317727479

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.