Cellular and Molecular Effects of Targeting the CBP/β-Catenin Interaction with PRI-724 in Melanoma Cells, Drug-Naïve and Resistant to Inhibitors of BRAFV600 and MEK1/2

Targeted therapies, including treatment with inhibitors of BRAF^V600 and MEK kinases, have improved outcomes in advanced melanoma. However, most patients relapse due to acquired resistance, underscoring the need for new drug targets. This study evaluated PRI-724, a CBP/β-catenin inhibitor, in patient-derived drug-naïve melanoma cells and their trametinib- or vemurafenib-resistant counterparts. While PRI-724 has demonstrated efficacy in preclinical models and clinical trials in different cancer types, its potential in melanoma has not been previously assessed. We found that treatment with PRI-724 downregulated survivin and other CBP/β-catenin target proteins, reduced invasiveness, and induced apoptosis in drug-naïve and trametinib- and vemurafenib-resistant cells. Trametinib-resistant melanoma cells showed the greatest sensitivity to PRI-724, indicating that CBP/β-catenin transcriptional activity may represent a new therapeutic vulnerability. Transcriptomic and immunoblotting analyses revealed the highest survivin levels in vemurafenib-resistant cells, which may underlie their reduced responsiveness to PRI-724. Bioinformatic analyses (TCGA and GSE50509) confirmed that a high survivin level predicts poor prognosis and reduced response to treatment. The results of the study point to the potential of PRI-724 as a chemotherapeutic agent for the treatment of melanoma. Its efficacy might depend on CBP/β-catenin transcriptional activity in melanoma cells, and further evaluation of this signaling with survivin as a biomarker is therefore warranted.