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.