TY - JOUR
T1 - A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer
AU - Dietlein, Felix
AU - Kalb, Bastian
AU - Jokic, Mladen
AU - Noll, Elisa M.
AU - Strong, Alexander
AU - Tharun, Lars
AU - Ozretić, Luka
AU - Künstlinger, Helen
AU - Kambartel, Kato
AU - Randerath, Winfried J.
AU - Jüngst, Christian
AU - Schmitt, Anna
AU - Torgovnick, Alessandro
AU - Richters, André
AU - Rauh, Daniel
AU - Siedek, Florian
AU - Persigehl, Thorsten
AU - Mauch, Cornelia
AU - Bartkova, Jirina
AU - Bradley, Allan
AU - Sprick, Martin R.
AU - Trumpp, Andreas
AU - Rad, Roland
AU - Saur, Dieter
AU - Bartek, Jiri
AU - Wolf, Jürgen
AU - Büttner, Reinhard
AU - Thomas, Roman K.
AU - Reinhardt, H. Christian
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/7/3
Y1 - 2015/7/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84934299233&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.05.053
DO - 10.1016/j.cell.2015.05.053
M3 - Article
C2 - 26140595
AN - SCOPUS:84934299233
SN - 0092-8674
VL - 162
SP - 146
EP - 159
JO - Cell
JF - Cell
IS - 1
ER -