Synergistic effects of combined Wnt/KRAS inhibition in colorectal cancer cells

PLoS One. 2012;7(12):e51449. doi: 10.1371/journal.pone.0051449. Epub 2012 Dec 5.

Abstract

Activation of Wnt signalling due to inability to degrade β-catenin is found in >85% of colorectal cancers. Approximately half of colon cancers express a constitutively active KRAS protein. A significant fraction of patients show both abnormalities. We previously reported that simultaneous down-regulation of both β-catenin and KRAS was necessary to induce significant cell death and tumor growth inhibition of colorectal cancer cells. Although attractive, an RNAi-based therapeutic approach is still far from being employed in the clinical setting. Therefore, we sought to recapitulate our previous findings by the use of small-molecule inhibitors of β-catenin and KRAS. We show here that the β-catenin inhibitors PKF115-584 and pyrvinium pamoate block β-catenin-dependent transcriptional activity and synergize with the KRAS inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS, salirasib) in colon cancer cells driven by Wnt and KRAS oncogenic signals, but not in cells carrying BRAF mutations. The combined use of these compounds was superior to the use of any drug alone in inducing cell growth arrest, cell death, MYC and survivin down-modulation, and inhibition of anchorage-independent growth. Expression analysis of selected cancer-relevant genes revealed down-regulation of CD44 as a common response to the combined treatments. These data provide a proof of principle for a combination therapeutic strategy in colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Drug Synergism
  • Farnesol / analogs & derivatives
  • Farnesol / chemistry
  • Farnesol / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Perylene / analogs & derivatives
  • Perylene / chemistry
  • Perylene / pharmacology
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Pyrvinium Compounds / chemistry
  • Pyrvinium Compounds / pharmacology
  • Salicylates / chemistry
  • Salicylates / pharmacology
  • Wnt Proteins / antagonists & inhibitors*
  • Wnt Proteins / metabolism
  • ras Proteins / antagonists & inhibitors*
  • ras Proteins / metabolism

Substances

  • KRAS protein, human
  • PKF115-584
  • Proto-Oncogene Proteins
  • Pyrvinium Compounds
  • Salicylates
  • Wnt Proteins
  • farnesylthiosalicylic acid
  • Farnesol
  • Perylene
  • pyrvinium
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins

Grant support

This work was supported by the Italian Association for Cancer Research (AIRC), Cariplo Foundation, the Italian Ministry of Health and Lombardy Regional Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.