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

被引:91
作者
Atkinson, Jennifer M. [1 ]
Rank, Kenneth B. [1 ]
Zeng, Yi [1 ]
Capen, Andrew [1 ]
Yadav, Vipin [1 ]
Manro, Jason R. [2 ]
Engler, Thomas A. [3 ]
Chedid, Marcio [1 ]
机构
[1] Eli Lilly & Co, Lilly Res Labs, Oncol Discovery Res, Indianapolis, IN 46285 USA
[2] Eli Lilly & Co, Lilly Res Labs, Stat Discovery, Indianapolis, IN 46285 USA
[3] Eli Lilly & Co, Lilly Res Labs, Discovery Chem Res & Technol, Indianapolis, IN 46285 USA
来源
PLOS ONE | 2015年 / 10卷 / 04期
关键词
BETA-CATENIN; TARGET; CANCER; EXPRESSION;
D O I
10.1371/journal.pone.0125028
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
It has previously been observed that a loss of beta-catenin expression occurs with melanoma progression and that nuclear beta-catenin levels are inversely proportional to cellular proliferation, suggesting that activation of the Wnt/beta-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 GSK3 alpha and GSK3 beta isoforms. In a panel of melanoma cell lines, nM concentrations of LY2090314 stimulated TCF/LEF TOP-Flash reporter activity, stabilized beta-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 similar to 10nM after 72hr of treatment) in contrast to other solid tumor cell lines (IC50 > 10 mu M) 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 beta-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 beta-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.
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页数:15
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