BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors
Autor: | Martin Mistrik, Radek Fedr, Ondřej Hylse, Jiří Kohoutek, Šárka Šimečková, Kamil Paruch, Juraj Kramara, Hana Paculová, Karel Souček, Marek Svoboda |
---|---|
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
DNA damage DNA repair Poly (ADP-Ribose) Polymerase-1 Synthetic lethality 03 medical and health sciences Mice Downregulation and upregulation Gene silencing Animals Humans Gene Silencing Gene Polymerase RC254-282 biology Chemistry Kinase BRCA1 Protein Neoplasms. Tumors. Oncology. Including cancer and carcinogens General Medicine HCT116 Cells Xenograft Model Antitumor Assays Cyclin-Dependent Kinases 3. Good health Gene Expression Regulation Neoplastic 030104 developmental biology Pyrimidines Drug Resistance Neoplasm Checkpoint Kinase 1 Cancer research biology.protein Pyrazoles Colorectal Neoplasms DNA Damage |
Zdroj: | Tumor Biology, Vol 39 (2017) |
ISSN: | 1423-0380 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |