Synergistic Effects of Combined Wnt/KRAS Inhibition in Colorectal Cancer Cells

• DOI: 10.1371/journal.pone.0051449
• Publication Date: 2012-12-05T19:25:25Z
• Authors: Luca Mologni; Stefania Brussolo; Monica Ceccon; Carlo Gambacorti-...
• Keywords: Survivin

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