Both the Wnt/β-catenin and Ras pathways are aberrantly activated in most human colorectal cancers (CRCs) and interact cooperatively in tumor promotion. Inhibition of these signaling may therefore be an ideal strategy for treating CRC. We identified KY1220, a compound that destabilizes both β-catenin and Ras, via targeting the Wnt/β-catenin pathway, and synthesized its derivative KYA1797K. KYA1797K bound directly to the regulators of G-protein signaling domain of axin, initiating β-catenin and Ras degradation through enhancement of the β-catenin destruction complex activating GSK3β. KYA1797K effectively suppressed the growth of CRCs harboring APC and KRAS mutations, as shown by various in vitro studies and by in vivo studies using xenograft and transgenic mouse models of tumors induced by APC and KRAS mutations. Destabilization of both β-catenin and Ras via targeting axin is a potential therapeutic strategy for treatment of CRC and other type cancers activated Wnt/β-catenin and Ras pathways.
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We thank B. Vogelstein, K.W. Kinzler, J.-W. Oh, N.-C. Ha and E.-h. Jho for providing cells and reagents. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (grants 2016R1A5A1004694, 2015R1A2A1A05001873). Y.-H.C. and S.C. were supported by a BK21 studentship from the NRF.
The authors declare no competing financial interests.
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Cha, PH., Cho, YH., Lee, SK. et al. Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation. Nat Chem Biol 12, 593–600 (2016). https://doi.org/10.1038/nchembio.2103
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