Small Molecule Destabilizer of β-Catenin and Ras Proteins Antagonizes Growth of K-Ras Mutation-Driven Colorectal Cancers Resistant to EGFR Inhibitors.

Abstract

Oncogenic K-Ras mutations in colorectal cancer (CRC) combined with APC mutations worsen CRC prognosis and lower drug effectiveness. Thus, inhibition of both Wnt/β-catenin and Ras-MAPK signaling may be a rational strategy to improve the treatment of this cancer. To identify a novel compound inhibiting both Wnt/β-catenin and Ras-MAPK signaling in CRC. We developed a two-part screening system consisting of analysis of TOP flash reporter cells and then potential toxicity effects on primary neural stem cells (NSCs). We then screened 2000 chemical compounds and tested efficacy of candidates against isogenic colon cancer cells harboring wild-type or mutant K-Ras. We employed immunohistochemistry and immunocytochemistry to determine marker signatures associated with development of disease phenotypes. We identified CPD0857, a compound that inactivates Wnt/β-catenin signaling and promotes ubiquitin-dependent proteasomal degradation of β-catenin and Ras proteins. CPD0857 effectively decreased proliferation and increased apoptosis of CRC cell lines, and overcame resistance of CRC harboring APC and K-Ras mutations to treatment with an EGFR monoclonal antibody (mAb). Moreover, CPD0857 attenuated invasiveness of highly migratory CRC cells in vitro. Accordingly, xenograft mice treated with CPD0857 showed slower tumor growth and significant decreases in both β-catenin and Ras protein expression. CPD0857 may be a potential drug for treating aggressive CRC carrying mutations that aberrantly activate Wnt/β-catenin and Ras-ERK pathways.