YAP Upregulation Contributes to Acquired Resistance to BET Inhibitors in Uveal Melanoma

Abstract

BET inhibitors have the potential to treat malignant tumors via the epigenetic modification mechanism. Although BET inhibitors show promise as anticancer agents for uveal melanoma (UM), the emergence of acquired resistance significantly limits their clinical efficacy. We developed isogenic OTX015-resistant UM cell models (OMM2.3R and OMM2.5R) via exposure to escalating OTX015 concentrations (0.04–0.5 μM over 6 months). These resistant cells demonstrated reduced sensitivity to OTX015-induced cytotoxicity. Moreover, the migratory ability of resistant cells was less affected by OTX015 compared to parental cells. Transcriptome analysis revealed an upregulation of YAP-activated genes in resistant cells. Notably, OTX015-resistant cells retained sensitivity to YAP inhibition via shRNA or pharmacological inhibitors. This study establishes YAP activation as a novel compensatory mechanism driving BET inhibitor resistance in UM. These findings position YAP inhibition as a potential therapeutic target to overcome BET inhibitor resistance, with clinical translational potential for resistant UM patients.