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

Anna Han, Timothy J. Purwin, Nelisa Bechtel, Connie Liao, Vivian Chua, Erin Seifert, Takami Sato, Zachary T. Schug, David W. Speicher, J. William Harbour, Andrew E. Aplin

Research output: Contribution to journalArticlepeer-review

Abstract

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 OXPHOShighBAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOSlowBAP1 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.

Original languageEnglish (US)
Pages (from-to)618-632
Number of pages15
JournalOncogene
Volume40
Issue number3
DOIs
StatePublished - Jan 21 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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