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

Cell. 2015 Jul 2;162(1):146-59. doi: 10.1016/j.cell.2015.05.053.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma of Lung
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Cycle Checkpoints
  • Checkpoint Kinase 1
  • DNA Damage
  • Disease Models, Animal
  • Drug Synergism*
  • Enzyme Inhibitors / pharmacology*
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Lung Neoplasms / drug therapy
  • Mice
  • Neoplasm Transplantation
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Tumor Cells, Cultured
  • ras Proteins / metabolism*

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Protein Kinases
  • MAP-kinase-activated kinase 2
  • BRAF protein, human
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins