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Cell. 2015 Jul 2;162(1):146-59. doi: 10.1016/j.cell.2015.05.053.

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

Author information

1
Department I of Internal Medicine, University Hospital Cologne, Weyertal 115B, 50931 Cologne, Germany; CECAD, University of Cologne, Weyertal 115B, 50931 Cologne, Germany. Electronic address: fdietlei@smail.uni-koeln.de.
2
Department I of Internal Medicine, University Hospital Cologne, Weyertal 115B, 50931 Cologne, Germany; CECAD, University of Cologne, Weyertal 115B, 50931 Cologne, Germany.
3
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.
4
The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
5
Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
6
Network Genomic Medicine, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany; Lungenklinik, Krankenhaus Bethanien Moers, Bethanienstraße 21, 47441 Moers, Germany.
7
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.
8
CECAD, University of Cologne, Weyertal 115B, 50931 Cologne, Germany.
9
Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
10
Department of Radiology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
11
Department of Dermatology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
12
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.
13
Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
14
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.
15
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 München, Germany.
16
Department I of Internal Medicine, University Hospital Cologne, Weyertal 115B, 50931 Cologne, Germany; Network Genomic Medicine, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
17
Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany; Network Genomic Medicine, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
18
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.
19
Department I of Internal Medicine, University Hospital Cologne, Weyertal 115B, 50931 Cologne, Germany; CECAD, University of Cologne, Weyertal 115B, 50931 Cologne, Germany. Electronic address: christian.reinhardt@uk-koeln.de.

Erratum in

  • Cell. 2015 Aug 27;162(5):1169.

Abstract

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.

Comment in

PMID:
26140595
DOI:
10.1016/j.cell.2015.05.053
[Indexed for MEDLINE]
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