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

TL;DR

This study explores the potential of PRI-724, a CBP/β-catenin inhibitor, to treat melanoma, including drug-resistant forms, by reducing cell survival and invasiveness.

Contribution

The study is the first to assess PRI-724's effects in melanoma, identifying CBP/β-catenin as a new therapeutic target.

Findings

PRI-724 reduced survivin and other CBP/β-catenin target proteins, inducing apoptosis in drug-naïve and resistant melanoma cells.

Trametinib-resistant cells showed the highest sensitivity to PRI-724, suggesting a new therapeutic vulnerability.

High survivin levels in vemurafenib-resistant cells correlated with reduced PRI-724 responsiveness and poor prognosis.

Abstract

Targeted therapies, including treatment with inhibitors of BRAFV600 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.

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