PLX209771

GSE100066: Transcriptome sequencing analysis of BRAF-mutant melanoma metastases.

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Melanoma patients carry a high risk of developing brain metastases, and improvements in survival are still measured in weeks or months. Durable disease control within the brain is impeded by poor drug penetration across the blood-brain barrier, as well as intrinsic and acquired drug resistance. In this study, we used high-throughput pharmacogenomic profiling to identify potentially repurposable compounds against BRAF-mutant melanoma brain metastases. One of the compounds identified was -sitosterol, a well-tolerated and brain-penetrable phytosterol. We found that -sitosterol attenuated melanoma cell growth in vitro and significantly inhibited brain metastasis in vivo. Large-scale phosphoproteomic and in silico analyses indicated that the therapeutic potential of -sitosterol was linked to mitochondrial interference. Mechanistically, -sitosterol effectively reduced mitochondrial respiration and respiratory capacity in melanoma cells, mediated by a selective inhibition of mitochondrial complex I. This led to increased oxidative stress and apoptosis. Notably, we observed completely abrogated BRAF inhibitor resistance when vemurafenib was combined with either -sitosterol or a functional knockdown of mitochondrial complex I. Based on its favorable tolerability, excellent brain bioavailability, and capacity to inhibit mitochondrial respiration, -sitosterol represents a promising candidate for drug repurposing in patients with, or at risk for, melanoma brain metastases. SOURCE: Clifford,G.,Tepper (cgtepper@ucdavis.edu) - UC Davis School of Medicine