| PACULOVÁ, Hana, Juraj KRAMARA, Šárka ŠIMEČKOVÁ, Radek FEDR, Karel SOUČEK, Ondřej HYLSE, Kamil PARUCH, Marek SVOBODA, Martin MISTRÍK and Jiří KOHOUTEK. BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors. Tumor Biology. Springer Netherlands, 2017, vol. 2017, October, p. 1-11. ISSN 1010-4283. Available from: https://dx.doi.org/10.1177/1010428317727479. |
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@article{1392816,
author = {Paculová, Hana and Kramara, Juraj and Šimečková, Šárka and Fedr, Radek and Souček, Karel and Hylse, Ondřej and Paruch, Kamil and Svoboda, Marek and Mistrík, Martin and Kohoutek, Jiří},
article_number = {October},
doi = {http://dx.doi.org/10.1177/1010428317727479},
keywords = {DNA damage response; BRCA1; CDK12; CHK1 inhibitor; transcription},
language = {eng},
issn = {1010-4283},
journal = {Tumor Biology},
title = {BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors},
url = {https://doi.org/10.1177/1010428317727479},
volume = {2017},
year = {2017}
}
TY - JOUR
ID - 1392816
AU - Paculová, Hana - Kramara, Juraj - Šimečková, Šárka - Fedr, Radek - Souček, Karel - Hylse, Ondřej - Paruch, Kamil - Svoboda, Marek - Mistrík, Martin - Kohoutek, Jiří
PY - 2017
TI - BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors
JF - Tumor Biology
VL - 2017
IS - October
SP - 1-11
EP - 1-11
PB - Springer Netherlands
SN - 10104283
KW - DNA damage response
KW - BRCA1
KW - CDK12
KW - CHK1 inhibitor
KW - transcription
UR - https://doi.org/10.1177/1010428317727479
N2 - 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.
ER -
PACULOVÁ, Hana, Juraj KRAMARA, Šárka ŠIMEČKOVÁ, Radek FEDR, Karel SOUČEK, Ondřej HYLSE, Kamil PARUCH, Marek SVOBODA, Martin MISTRÍK and Jiří KOHOUTEK. BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors. \textit{Tumor Biology}. Springer Netherlands, 2017, vol.~2017, October, p.~1-11. ISSN~1010-4283. Available from: https://dx.doi.org/10.1177/1010428317727479.
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