A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer (CROSBI ID 219765)
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Podaci o odgovornosti
Dietlein, F. ; Kalb, B. ; Jokić, Mladen ; Noll, E.M. ; Strong, A. ; Tharun, L. ; Ozretić, Luka ; Künstlinger, H. ; Kambartel, K. ; Randerath, W.J. ; Jüngst, C. ; Schmitt, A. ; Torgovnick, A. ; Richters, A. ; Rauh, D. ; Siedek, F. ; Persigehl, T. ; Mauch, C. ; Bartkova, J. ; Bradley, A. ; Sprick, M.R. ; Trumpp, A. ; Rad, R. ; Saur, D. ; Bartek, J. ; Wolf, J. ; Büttner, R. ; Thomas, R.K. ; Reinhardt, H.C.
engleski
A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer
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.
synergism; Chk-1; MK2; Kras; cancer
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