A Synergistic Interaction between Chk1-and MK2 Inhibitors in KRAS-Mutant Cancer
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
A Synergistic Interaction between Chk1-and MK2 Inhibitors in KRAS-Mutant Cancer
Original language description
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
Czech name
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Czech description
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Classification
Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
EB - Genetics and molecular biology
OECD FORD branch
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Result continuities
Project
<a href="/en/project/LO1304" target="_blank" >LO1304: Support of suistainability of the Institute of Molecular and Translational Medicine</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2015
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Cell
ISSN
0092-8674
e-ISSN
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Volume of the periodical
162
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
146-159
UT code for WoS article
000357542300016
EID of the result in the Scopus database
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