Disrupting the CBP/ ß-catenin Axis: A Path to Suppress Survivin and Induce Apoptosis in Melanoma

Survivin, the member of the inhibitors of apoptosis (IAP) protein family is overexpressed in various cancer types while remaining nearly undetectable in normal cells. Survivin overexpression is associated with increased chemotherapy resistance, tumor recurrence, and shorter patient survival. Bioinformatics analysis supported the observation that increased expression of survivin may be a biomarker of poorer patients' survival and may contribute to resistance to standard targeted therapy of melanoma. The lack of identifiable active sites and enzymatic activity make targeting survivin challenging. Therefore, indirect targeting of survivin may represent a feasible therapeutic approach. To downregulate survivin, we used PRI-724, an inhibitor of CBP/ß-catenin signaling axis. While PRI-724 has demonstrated efficacy in preclinical models and clinical trials in different cancer types, its potential in melanoma had not been previously assessed. Treatment of drug-naïve, trametinib- and vemurafenib-resistant melanoma cells with PRI-724 was sufficient to downregulate survivin and other CBP/ß-catenin target proteins, inhibit proliferation, reduce invasiveness and induce apoptosis. These findings indicated that PRI-724 exhibited significant antitumor activity in both drug-naïve melanoma cells and their drug-resistant counterparts. Among the resistant populations, trametinib-resistant melanoma cells showed the greatest sensitivity to PRI-724 treatment, whereas vemurafenib-resistant melanoma cells, which exhibited the higher expression of survivin, were the less responsive to PRI-724 treatment. Overall design: RNA-seq data was prepared from DMBC21 patient-derived melanoma cell lines and their drug-resistant counterparts: cells with acquired resistance to vemurafenib (DMBC21PLXR) and trametinib (DMBC21TRAR)