Identification of Ras-degrading small molecules that inhibit the transformation of colorectal cancer cells independent of β-catenin signaling

Abstract

Colorectal cancer: Finding new small molecule drug candidates Mutations in KRAS, a gene regulating cell proliferation, occur in 40–50% of colorectal cancer (CRC) patients. These cancers are usually insensitive to antibody drugs targeting the epidermal growth factor receptor (EGFR) on cancer cells. Kang-Yell Choi at Yonsei University, Seoul, South Korea and co-workers had previously identified small molecules that inhibited CRC by degrading the signaling proteins β-catenin and Ras. However, CRC cells with β-catenin mutations are resistant to Ras-degrading compounds. In this study, they screened 10,000 small molecules that could degrade Ras in CRC cells expressing nondegradable mutant β-catenin. They identified small molecules that inhibited growth of CRC cells resistant to EGFR-mediated antibody therapy. Further investigation of these molecules may help develop new drugs for treating CRC.