Identification of Ras-degrading small molecules that inhibit the transformation of colorectal cancer cells independent of β-catenin signaling
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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/β-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 β-catenin and Ras. Due to the absence of Ras degradation in cells expressing a nondegradable mutant form of β-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/β-catenin signaling pathway. A cell-based high-content screening (HCS) system that monitors the levels of EGFP-K-RasG12V was established using HCT-116 cells harboring a nondegradable mutant CTNNB1 (ΔS45). 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 β-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 β-catenin may able to be used in treatments for cancers caused by aberrant EGFR and Ras. 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.
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Small chemical compounds such as KY7749 and methylglyoxal scavengers resensitize KRAS-mutated colorectal cancer cells to cetuximab in vivo.
“In addition, small chemical compounds such as KY7749 and methylglyoxal scavengers resensitize KRAS-mutated CRC cells to cetuximab in vivo [48, 89].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [89]
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- Authors
- Shin, W., Lee, S.-K., Hwang, J.-H., Park, J.-C., Cho, Y.-H., Ro, E. J., Song, Y., Seo, H. R., & Choi, K.-Y.
- Affiliations
- Yonsei University (KR)
- Institut Pasteur Korea (KR)
- Corresponding author
- Choi, Kang-Yell
- Venue
- Experimental & Molecular Medicine
- Published
- 2018-06
- Volume
- 50
- Issue
- 6
- Pages
- 1-10
- ISSN
- 1226-3613 (ISSN-L)
- 2092-6413
- PMC
- PMC5994827
- OpenAlex
- W2805041634
- Cited by
- 10
- References
- 36
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 4
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Experimental & Molecular Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Research Foundation of Korea (2015R1A2A1A05001873, 2016R1A5A1004694)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- colorectal cancer, small molecule inhibitors, Wnt/β-catenin signaling, KRAS mutation, cetuximab resistance, EGFR, HCT116 cells, cell transformation, drug discovery
- MeSH terms
- Antineoplastic Agents, Drug Screening Assays, Antitumor, Humans, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), HCT116 Cells, beta Catenin, Proteolysis, Wnt Signaling Pathway, ErbB Receptors
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