Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma – Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3
Fig 4
LY2090314 demonstrates activity in cell lines resistant to the BRAF inhibitor Vemurafenib and has an independent mechanism of action.
A. Wild type melanoma cell lines M14 and A375 are sensitive to growth inhibition by Vemurafenib relative to cells selected as resistant to Vemurafenib. However, LY2090314 retains potency in both wild type and Vemurafenib resistant cell lines (● A375 control; ■ Vemurafenib resistant A375; ▲ M14 control; ▼ Vemurafenib resistant M14). B. In a panel of melanoma cell lines, variable sensitivity to Vemurafenib can be observed using 72 hr cytotoxicity assays whilst all cells tested displayed sensitivity to LY2090314. C. LY2090314 and Vemurafenib have distinct mechanisms of action. Following drug treatment, cells were analyzed for compound effect on the Wnt and Ras pathways and demonstrate differential signaling pathway modulation.