Dietlein, Felix, Kalb, Bastian, Jokic, Mladen, Noll, Elisa M., Strong, Alexander, Tharun, Lars, Ozretic, Luka, Kuenstlinger, Helen, Kambartel, Kato, Randerath, Winfried J., Juengst, Christian, Schmitt, Anna, Torgovnick, Alessandro, Richters, Andre, Rauh, Daniel ORCID: 0000-0002-1970-7642, Siedek, Florian, Persigehl, Thorsten, Mauch, Cornelia, Bartkova, Jirina, Bradley, Allan ORCID: 0000-0002-2349-8839, Sprick, Martin R. ORCID: 0000-0001-9691-7574, Trumpp, Andreas ORCID: 0000-0002-6212-3466, Rad, Roland, Saur, Dieter ORCID: 0000-0001-5874-0210, Bartek, Jiri, Wolf, Juergen, Buettner, Reinhard, Thomas, Roman K. and Reinhardt, H. Christian (2015). A Synergistic Interaction between Chk1-and MK2 Inhibitors in KRAS-Mutant Cancer. Cell, 162 (1). S. 146 - 160. CAMBRIDGE: CELL PRESS. ISSN 1097-4172

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dietlein, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalb, BastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jokic, MladenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noll, Elisa M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strong, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tharun, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozretic, LukaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuenstlinger, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kambartel, KatoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Randerath, Winfried J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Juengst, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torgovnick, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richters, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDorcid.org/0000-0002-1970-7642UNSPECIFIED
Siedek, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mauch, CorneliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartkova, JirinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bradley, AllanUNSPECIFIEDorcid.org/0000-0002-2349-8839UNSPECIFIED
Sprick, Martin R.UNSPECIFIEDorcid.org/0000-0001-9691-7574UNSPECIFIED
Trumpp, AndreasUNSPECIFIEDorcid.org/0000-0002-6212-3466UNSPECIFIED
Rad, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saur, DieterUNSPECIFIEDorcid.org/0000-0001-5874-0210UNSPECIFIED
Bartek, JiriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-399064
DOI: 10.1016/j.cell.2015.05.053
Journal or Publication Title: Cell
Volume: 162
Number: 1
Page Range: S. 146 - 160
Date: 2015
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4172
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL-CYCLE; REVEALS; MODELMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/39906

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