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.

CECAD University of Cologne Weyertal 115B 50931 Cologne Germany

Danish Cancer Society Research Center Strandboulevarden 49 2100 Copenhagen Denmark; Institute of Molecular and Translational Medicine Palacky University Hněvotínská 1333 5 77900 Olomouc Czech Republic; Science for Life Laboratory Division of Translational Medicine and Chemical Biology Department of Medical Biochemistry and Biophysics Karolinska Institute 17177 Stockholm Sweden

Department 1 of Internal Medicine University Hospital Cologne Weyertal 115B 50931 Cologne Germany; CECAD University of Cologne Weyertal 115B 50931 Cologne Germany

Department 1 of Internal Medicine University Hospital Cologne Weyertal 115B 50931 Cologne Germany; Network Genomic Medicine University Hospital Cologne Kerpener Strasse 62 50937 Cologne Germany

Department of Chemistry and Chemical Biology Technische Universität Dortmund Otto Hahn Strasse 6 44227 Dortmund Germany

Department of Dermatology University Hospital Cologne Kerpener Strasse 62 50937 Cologne Germany

Department of Internal Medicine 2 Klinikum rechts der Isar Technische Universität München Ismaninger Strasse 22 81675 München Germany

Department of Radiology University Hospital Cologne Kerpener Strasse 62 50937 Cologne Germany

Division of Stem Cells and Cancer Deutsches Krebsforschungszentrum Im Neuenheimer Feld 280 69120 Heidelberg Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine Im Neuenheimer Feld 280 69120 Heidelberg Germany

Division of Stem Cells and Cancer Deutsches Krebsforschungszentrum Im Neuenheimer Feld 280 69120 Heidelberg Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine Im Neuenheimer Feld 280 69120 Heidelberg Germany; German Cancer Consortium Im Neuenheimer Feld 280 69120 Heidelberg Germany

Heidelberg Institute for Stem Cell Technology and Experimental Medicine Im Neuenheimer Feld 280 69120 Heidelberg Germany

Institute of Pathology University Hospital Cologne Kerpener Strasse 62 50937 Cologne Germany

Institute of Pathology University Hospital Cologne Kerpener Strasse 62 50937 Cologne Germany; Department of Translational Genomics Medical Faculty University of Cologne Weyertal 115B 50931 Cologne Germany

Institute of Pathology University Hospital Cologne Kerpener Strasse 62 50937 Cologne Germany; Network Genomic Medicine University Hospital Cologne Kerpener Strasse 62 50937 Cologne Germany

Network Genomic Medicine University Hospital Cologne Kerpener Strasse 62 50937 Cologne Germany; Klinik für Pneumologie Krankenhaus Bethanien Solingen Aufderhöher Strasse 169 175 42699 Solingen Germany

Network Genomic Medicine University Hospital Cologne Kerpener Strasse 62 50937 Cologne Germany; Lungenklinik Krankenhaus Bethanien Moers Bethanienstraße 21 47441 Moers Germany

The Wellcome Trust Sanger Institute Genome Campus Hinxton Cambridge CB10 1SA UK

Cell. 2015 Aug 27;162(5):1169 PubMed

Nat Rev Drug Discov. 2015 Sep;14(9):600-1. doi: 10.1038/nrd4710. PubMed

Citace poskytuje Crossref.org

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