BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F17%3A00067247" target="_blank" >RIV/00159816:_____/17:00067247 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14310/17:00097945 RIV/61989592:15110/17:73584999 RIV/00027162:_____/17:N0000131

Výsledek na webu

<a href="http://dx.doi.org/10.1177/1010428317727479" target="_blank" >http://dx.doi.org/10.1177/1010428317727479</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1177/1010428317727479" target="_blank" >10.1177/1010428317727479</a>

Jazyk výsledku

angličtina

Název v původním jazyce

BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

Popis výsledku anglicky

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.

Druh

J_ost - Ostatní články v recenzovaných periodicích

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Tumor Biology

ISSN

1010-4283

e-ISSN

—

Svazek periodika

39

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

11

Strana od-do

1-11

Kód UT WoS článku

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EID výsledku v databázi Scopus

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