Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3.

Autor: Atkinson JM; Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America., Rank KB; Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America., Zeng Y; Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America., Capen A; Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America., Yadav V; Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America., Manro JR; Statistics Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America., Engler TA; Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America., Chedid M; Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2015 Apr 27; Vol. 10 (4), pp. e0125028. Date of Electronic Publication: 2015 Apr 27 (Print Publication: 2015).
DOI: 10.1371/journal.pone.0125028
Abstrakt: It has previously been observed that a loss of β-catenin expression occurs with melanoma progression and that nuclear β-catenin levels are inversely proportional to cellular proliferation, suggesting that activation of the Wnt/β-catenin pathway may provide benefit for melanoma patients. In order to further probe this concept we tested LY2090314, a potent and selective small-molecule inhibitor with activity against GSK3α and GSK3β isoforms. In a panel of melanoma cell lines, nM concentrations of LY2090314 stimulated TCF/LEF TOPFlash reporter activity, stabilized β-catenin and elevated the expression of Axin2, a Wnt responsive gene and marker of pathway activation. Cytotoxicity assays revealed that melanoma cell lines are very sensitive to LY2090314 in vitro (IC50 ~10 nM after 72hr of treatment) in contrast to other solid tumor cell lines (IC50 >10 uM) as evidenced by caspase activation and PARP cleavage. Cell lines harboring mutant B-RAF or N-RAS were equally sensitive to LY2090314 as were those with acquired resistance to the BRAF inhibitor Vemurafenib. shRNA studies demonstrated that β-catenin stabilization is required for apoptosis following treatment with the GSK3 inhibitor since the sensitivity of melanoma cell lines to LY290314 could be overcome by β-catenin knockdown. We further demonstrate that in vivo, LY2090314 elevates Axin2 gene expression after a single dose and produces tumor growth delay in A375 melanoma xenografts with repeat dosing. The activity of LY2090314 in preclinical models suggests that the role of Wnt activators for the treatment of melanoma should be further explored.
Databáze: MEDLINE
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