期刊
CELL
卷 162, 期 1, 页码 146-159出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.05.053
关键词
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资金
- Volkswagenstiftung (Lichtenberg Program)
- Deutsche Forschungsgemeinschaft [KFO-286, RE2246/2-1]
- Helmholtz-Gemeinschaft (Preclinical Comprehensive Cancer Center)
- Boehringer Ingelheim Foundation
- German Cancer Aid [DKH-111112]
- Federal Ministry for Research and Education (BMBF) [01ZX1303A]
- Else Kroner-Fresenius Stiftung [EKFS-2014-A06]
- Dietmar Hopp Foundation
- Danish Cancer Society
- Lundbeck Foundation [R93-A8990]
- Czech National Program of Sustainability [LO1304]
- Danish National Research Foundation
- Lundbeck Foundation [R93-2011-8990] Funding Source: researchfish
- Novo Nordisk Fonden [NNF12OC0002290] Funding Source: researchfish
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- and MK2 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 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.
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