title: A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer.
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.
authors.affiliation: 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.
authors.forename: Felix
authors.initials: F
authors.lastname: Dietlein
authors.affiliation: Department I of Internal Medicine, University Hospital Cologne, Weyertal 115B, 50931 Cologne, Germany; CECAD, University of Cologne, Weyertal 115B, 50931 Cologne, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Kalb
authors.affiliation: Department I of Internal Medicine, University Hospital Cologne, Weyertal 115B, 50931 Cologne, Germany; CECAD, University of Cologne, Weyertal 115B, 50931 Cologne, Germany.
authors.forename: Mladen
authors.initials: M
authors.lastname: Jokic
authors.affiliation: 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.
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Noll
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Strong
authors.affiliation: Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Tharun
authors.affiliation: Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Ozretić
authors.affiliation: Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Künstlinger
authors.affiliation: Network Genomic Medicine, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany; Lungenklinik, Krankenhaus Bethanien Moers, Bethanienstraße 21, 47441 Moers, Germany.
authors.forename: Kato
authors.initials: K
authors.lastname: Kambartel
authors.affiliation: 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.
authors.forename: Winfried J
authors.initials: WJ
authors.lastname: Randerath
authors.affiliation: CECAD, University of Cologne, Weyertal 115B, 50931 Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jüngst
authors.affiliation: Department I of Internal Medicine, University Hospital Cologne, Weyertal 115B, 50931 Cologne, Germany; CECAD, University of Cologne, Weyertal 115B, 50931 Cologne, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: Department I of Internal Medicine, University Hospital Cologne, Weyertal 115B, 50931 Cologne, Germany; CECAD, University of Cologne, Weyertal 115B, 50931 Cologne, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Torgovnick
authors.affiliation: Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Richters
authors.affiliation: Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
authors.affiliation: Department of Radiology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Siedek
authors.affiliation: Department of Radiology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Persigehl
authors.affiliation: Department of Dermatology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.affiliation: 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.
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Sprick
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 München, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 München, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: 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.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: 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.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany; Network Genomic Medicine, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: 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.
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: H Christian
authors.initials: HC
authors.lastname: Reinhardt
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004195:Disease Models, Animal; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D009368:Neoplasm Transplantation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000970:Antineoplastic Agents; D000071877:Checkpoint Kinase 1; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000099190:MAP-Kinase-Activated Kinase 2; C117307:KRAS protein, human; C482119:BRAF protein, human; C000605867:CHEK1 protein, human; C000605869:Chek1 protein, mouse