KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer

Oncotarget. 2016 Dec 6;7(49):81727-81740. doi: 10.18632/oncotarget.13172.

Abstract

APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β-catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis. As shown by in vitro and in vivo studies using APCMin/+/K-RasG12DLA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. A small molecular approach degrading both β-catenin and Ras via inhibition of the Wnt/β-catenin signaling would be an ideal strategy for treatment of mCRC.

Keywords: Apc mutation; K-Ras mutation; Ras destabilizer; metastatic colorectal cancer; tumor budding.

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / metabolism
  • Actin Cytoskeleton / pathology
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / secondary
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / drug effects
  • Genes, APC
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Neoplasm Invasiveness
  • Protein Stability
  • Proteolysis
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Thiohydantoins / pharmacology*
  • Time Factors
  • Wnt Signaling Pathway / drug effects*
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Antineoplastic Agents
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • KRAS protein, human
  • KY1220
  • Thiohydantoins
  • beta Catenin
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)