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

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 OXPHOS high or OXPHOS low subgroups. Integrated RNA sequencing, metabolomics and molecular analyses showed that OXPHOS high BAP1 mutant UM

Oncogenic Gq/11 signaling acutely drives and chronically sustains metabolic reprogramming in uveal melanoma

“…5 and 8A). Thus, while BAP1 status may modify some aspects of metabolism (24,25), BAP1 is dispensable for oncogenic Gq/11 signaling to drive glycolytic and respiratory reprogramming in UM. Oncogenic Gq/11 signaling drives glucose uptake and glycolysis.…”

“…Such evidence and the poor prognosis of metastatic UM because of ineffective therapy ( 22 , 23 ) have motivated studies to elucidate molecular mechanisms of metabolic reprogramming that potentially could open new avenues for therapeutic discovery ( 11 ). Studies thus far have shown that metastatic risk associated with monosomy of chromosome 3 in UM correlates with greater mitochondrial activity and resistance to OxPhos inhibitors ( 24 ), and that UM cell lines lacking the BRCA1-associated protein 1 ( BAP1 ) metastasis suppressor can be stratified by metabolic phenotypes and differential sensitivity to metabolic inhibitors ( 25 ).…”

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

“…Even though Tebentafusp showed promising results in all UM patients, new studies will be instrumental to better define which UM biomarkers could be helpful to predict an enhanced positive response to this promising drug. Our increased knowledge on the mechanisms underlying UM development, including aspects of metabolomics [ 381 ] and of immune checkpoint inhibition, coupled with novel drug screening efforts taking advantage of robust pre-clinical models will hopefully, in the near future, lead to the development of efficacious therapeutic approaches against UM.…”

Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma

“…If metastasis occurs, the average overall survival is less than 1 year 18 . Several oncogenic factors have been found in UM, such as GNAQ/11 mutation, YAP/TAZ pathway activation, BAP1 deletion and chromosomal anomalies 17,19 . In addition, CM is a rare but sight‐ and life‐threatening malignancy that shows a distinct pattern of gene expression compared to uveal and cutaneous melanoma 20 .…”

“… 18 Several oncogenic factors have been found in UM, such as GNAQ/11 mutation, YAP/TAZ pathway activation, BAP1 deletion and chromosomal anomalies. 17 , 19 In addition, CM is a rare but sight‐ and life‐threatening malignancy that shows a distinct pattern of gene expression compared to uveal and cutaneous melanoma. 20 The BRAF V600E mutation, aberrant expression of microRNAs and dysregulated m6A RNA modifications, has been identified.…”