Discovery of SOX10 as a Key Pharmacodynamic Marker of BRM/BRG1 Inhibition in Uveal Melanoma

Abstract

Epigenetic dysregulation plays a fundamental role in the development of cancer. Chromatin remodeling complexes are major epigenetic modifiers, and defects in its activity has emerged as an important feature causing aberrant regulation of transcription in many cancers. BRG1, a catalytic subunit of SWI/SNF chromatin remodeling complex, is mutated in more than 20% of cancers, and synthetic lethal relationship with its paralog BRM points to the potential of BRM and BRG1 as therapeutic targets. Here we demonstrate that a small molecule BRM and BRG1 dual inhibitor Compound-FHT induces growth defect and apoptosis in uveal melanoma models. RNA-seq revealed SOX10 as a gene significantly downregulated in response to BRM and BRG1 inhibition, and genetic studies have revealed its key role in mediating Compound-FHT induced growth defect. Together, these results provide promise of pharmacological inhibition of BRM and BRG1 as a therapeutic approach for uveal melanoma, and SOX10 as a biomarker of pharmacodynamic response.