A variety of therapeutic options for melanoma have been developed since 2011, changing the way advanced melanomas are treated. Some treatments focus on specific mutations found in melanoma patients, such as BRAFV600E or BRAF V600K, but not all patients carry these mutations. When patients present BRAF mutation-negative melanomas they often fail on BRAF inhibitor medications, stimulating research to treat these patients with alternative therapies.
As a cancer, melanoma shares the feature of overactive cell proliferation. Excess cell proliferation has been liked to the nuclear protein β-catenin in the Wnt cell signaling pathway, where β-catenin levels are inversely related to cell proliferation. Accordingly, a group from the Oncology Discovery Research Department in Lilly Research Laboratories at Eli Lilly and Company is looking at ways to increase the level of nuclear β-catenin in melanoma cells.
Described in a recent report published in PLOS One entitled, “Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma – Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3,” the group used a molecule known as LY2090314 that was developed by the company to stabilize β-catenin. LY2090314 inhibits both isoforms of the protein glycogen synthase kinase-3, which inhibits β-catenin nuclear translocation. Effectively, by blocking an inhibitor of β-catenin, LY2090314 allows the protein to have an efficient nuclear activity.
When testing LY2090314 in melanoma cells in vitro, the group needed to apply only minuscule amounts (nanomolar concentrations) of LY2090314 to observe an effect. The drug led to gene expression associated with β-catenin activity that subsequently led to melanoma cell apoptosis.
While BRAF inhibitors are only effective in the case of BRAF mutations, LY2090314 proved to be effective regardless of BRAF mutation status. It was effective against cells that had become resistant to Vemurafenib, a BRAF inhibitor effective against BRAFV600E melanoma types. Either normal or BRAF-mutated melanoma cells underwent apoptosis when exposed to LY2090314. Furthermore, the authors observed there was no synergy between the two treatments.
On the other hand, LY2090314 showed synergy with dacabarzine (DTIC), a therapy approved before 2011 to treat metastatic melanoma. Tumor-bearing mice treated with the combination therapy saw a reduced progression of their cancerous tumors.
“The studies presented here provide proof-of-concept data supporting the use of Wnt activators in the treatment of melanoma and support further investigation of GSK3 inhibitors for melanoma therapy with particular attention given to the effects on healthy tissues,” concluded the authors.