A Synergistic Interaction between Chk1-and MK2 Inhibitors in KRAS-Mutant Cancer

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F15%3A33155702" target="_blank" >RIV/61989592:15110/15:33155702 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1016/j.cell.2015.05.053" target="_blank" >http://dx.doi.org/10.1016/j.cell.2015.05.053</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.cell.2015.05.053" target="_blank" >10.1016/j.cell.2015.05.053</a>

Jazyk výsledku

angličtina

Název v původním jazyce

A Synergistic Interaction between Chk1-and MK2 Inhibitors in KRAS-Mutant Cancer

Popis výsledku v původním jazyce

KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- andMK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhi

Název v anglickém jazyce

A Synergistic Interaction between Chk1-and MK2 Inhibitors in KRAS-Mutant Cancer

Popis výsledku anglicky

KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- andMK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhi

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

EB - Genetika a molekulární biologie

OECD FORD obor

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Projekt

<a href="/cs/project/LO1304" target="_blank" >LO1304: Podpora udržitelnosti Ústavu molekulární a translační medicíny</a><br>

Návaznosti

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

Rok uplatnění

2015

Kód důvěrnosti údajů

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

Název periodika

Cell

ISSN

0092-8674

e-ISSN

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Svazek periodika

162

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

146-159

Kód UT WoS článku

000357542300016

EID výsledku v databázi Scopus

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