BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors
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 homologo...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2017-10-01
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| Series: | Tumor Biology |
| Online Access: | https://doi.org/10.1177/1010428317727479 |
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| _version_ | 1849248142414839808 |
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| author | Hana Paculová Juraj Kramara Šárka Šimečková Radek Fedr Karel Souček Ondřej Hylse Kamil Paruch Marek Svoboda Martin Mistrík Jiří Kohoutek |
| author_facet | Hana Paculová Juraj Kramara Šárka Šimečková Radek Fedr Karel Souček Ondřej Hylse Kamil Paruch Marek Svoboda Martin Mistrík Jiří Kohoutek |
| author_sort | Hana Paculová |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e7bcbdc4ad754e1e8d403ed31b65297e |
| institution | Kabale University |
| issn | 1423-0380 |
| language | English |
| publishDate | 2017-10-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Tumor Biology |
| spelling | doaj-art-e7bcbdc4ad754e1e8d403ed31b65297e2025-08-20T03:58:03ZengSAGE PublishingTumor Biology1423-03802017-10-013910.1177/1010428317727479BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitorsHana Paculová0Juraj Kramara1Šárka Šimečková2Radek Fedr3Karel Souček4Ondřej Hylse5Kamil Paruch6Marek Svoboda7Martin Mistrík8Jiří Kohoutek9Department of Chemistry and Toxicology, Veterinary Research Institute, Brno, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech RepublicDepartment of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech RepublicInternational Clinical Research Center, St. Anne’s University Hospital, Brno, Czech RepublicInternational Clinical Research Center, St. Anne’s University Hospital, Brno, Czech RepublicDepartment of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech RepublicDepartment of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech RepublicDepartment of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech RepublicDepartment of Chemistry and Toxicology, Veterinary Research Institute, Brno, Czech RepublicA 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.https://doi.org/10.1177/1010428317727479 |
| spellingShingle | Hana Paculová Juraj Kramara Šárka Šimečková Radek Fedr Karel Souček Ondřej Hylse Kamil Paruch Marek Svoboda Martin Mistrík Jiří Kohoutek BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors Tumor Biology |
| title | BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors |
| title_full | BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors |
| title_fullStr | BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors |
| title_full_unstemmed | BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors |
| title_short | BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors |
| title_sort | brca1 or cdk12 loss sensitizes cells to chk1 inhibitors |
| url | https://doi.org/10.1177/1010428317727479 |
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