BAP1 mutant uveal melanoma is stratified by metabolic phenotypes with distinct vulnerability to metabolic inhibitors

Cancer cell metabolism is a targetable vulnerability; however, a precise understanding of metabolic heterogeneity is required. Inactivating mutations in BRCA1-associated protein 1 (BAP1) are associated with metastasis in uveal melanoma (UM), the deadliest adult eye cancer. BAP1 functions in UM remain unclear. UM patient sample analysis divided BAP1 mutant UM tumors into two subgroups based on oxidative phosphorylation (OXPHOS) gene expression suggesting metabolic heterogeneity. Consistent with patient data, transcriptomic analysis of BAP1 mutant UM cell lines also showed OXPHOShigh or OXPHOSlow subgroups. Integrated RNA sequencing, metabolomics, and molecular analyses showed that OXPHOS(high)BAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOS(low)BAP1 mutant UM cells employ fatty acid oxidation. Furthermore, the two subgroups responded to different classes of metabolic suppressors. Our findings indicate that targeting cancer metabolism is a promising therapeutic option for BAP1 mutant UM; however, tailored approaches may be required due to metabolic heterogeneities.

Automated summary

Cancer cell metabolism in BAP1 mutant uveal melanoma shows heterogeneity with distinct usage of metabolic pathways. Targeting cancer metabolism could be a promising therapeutic option, but tailored approaches are needed due to metabolic heterogeneities in BAP1 mutant UM. Overall, understanding metabolic diversity is crucial for developing effective treatment strategies.