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

Felix Dietlein, Bastian Kalb, Mladen Jokic, Elisa M. Noll, Alexander Strong, Lars Tharun, Luka Ozretić, Helen Künstlinger, Kato Kambartel, Winfried J. Randerath, Christian Jüngst, Anna Schmitt, Alessandro Torgovnick, André Richters, Daniel Rauh, Florian Siedek, Thorsten Persigehl, Cornelia Mauch, Jirina Bartkova, Allan BradleyMartin R. Sprick, Andreas Trumpp, Roland Rad, Dieter Saur, Jiri Bartek, Jürgen Wolf, Reinhard Büttner, Roman K. Thomas, H. Christian Reinhardt

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Summary 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.

Original languageEnglish
Pages (from-to)146-159
Number of pages14
JournalCell
Volume162
Issue number1
DOIs
StatePublished - 3 Jul 2015

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