Journal
EXPERIMENTAL AND MOLECULAR MEDICINE
Volume 50, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s12276-018-0102-5
Keywords
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Funding
- National Research Foundation of Korea (NRF) grant - Korean Government (MSIP) [2016R1A5A1004694, 2015R1A2A1A05001873]
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Although the development of drugs that control Ras is an emerging topic in cancer therapy, no clinically applicable drug is currently available. We have previously utilized knowledge of the Wnt/beta-catenin signaling-dependent mechanism of Ras protein stability regulation to identify small molecules that inhibit the proliferation and transformation of various colorectal cancer (CRC) cells via degradation of both beta-catenin and Ras. Due to the absence of Ras degradation in cells expressing a nondegradable mutant form of beta-catenin and the need to determine an alternative mechanism of Ras degradation, we designed a cell-based system to screen compounds that degrade Ras independent of the Wnt/beta-catenin signaling pathway. A cell-based high-content screening (HCS) system that monitors the levels of EGFP-K-Ras(G12V) was established using HCT-116 cells harboring a nondegradable mutant CTNNB1 (Delta S45). Through HCS of a chemical library composed of 10,000 compounds and subsequent characterization of hits, we identified several compounds that degrade Ras without affecting the beta-catenin levels. KY7749, one of the most effective compounds, inhibited the proliferation and transformation of CRC cells, especially KRAS-mutant cells that are resistant to the EGFR monoclonal antibody cetuximab. Small molecules that degrade Ras independent of beta-catenin may able to be used in treatments for cancers caused by aberrant EGFR and Ras.
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