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

◥Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK-ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) and cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in patients with estrogen receptor (ER)-positive breast cancer in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in uveal melanoma. In vitro, palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell-cycle proteins. In contrast, in vivo CDK4/ 6 inhibition alone led to cytostasis and was as effective as MEKi plus CDK4/6i treatment at delaying tumor growth. RNA sequencing revealed upregulation of the oxidative phosphorylation (OxPhos) pathway in both MEKi-resistant tumors and CDK4/6i-tolerant tumors. Furthermore, oxygen consumption rate was increased following MEKi þ CDK4/6i treatment. IACS-010759, an OxPhos inhibitor, decreased uveal melanoma cell survival in combination with MEKi þ CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi þ CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations.

UM represents approximately 5% of melanoma cases (Kaliki & Shields, 2017). Despite the low incidence of UM, which is diagnosed in ~2,000 adults annually in the United States, about 50% of patients develop metastasis that arises primarily in the liver (Diener-West et al., 2005). Following diagnosis of metastatic UM, disease prognosis is usually poor and median survival is 6-12 months (Krantz et al., 2017). The poor outcomes are largely due to ineffective responses of metastatic UM to targeted therapies such as chemotherapy and MEK inhibitors, and immunotherapies (Chua et al., 2021). By contrast, targeted therapies and immunotherapies have been successful in the treatment of subsets of cutaneous melanoma.Mechanisms controlling the metastasis of UM are unclear; however, studies have classified UM subtypes based on genetic and chromosomal aberration profiles and identified major alterations

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BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene that is mutated in cancer, including uveal melanoma (UM). Loss-of-function BAP1 mutations are associated with UM metastasis and poor prognosis, but the mechanisms underlying these effects remain unclear. Upregulation of cell-cell adhesion proteins is involved with collective migration and metastatic seeding of cancer cells. Here, we show that BAP1 loss in UM patient samples is associated with upregulated gene expression of multiple cell adhesion molecules (CAMs), including E-cadherin (CDH1), cell adhesion molecule 1 (CADM1), and syndecan-2 (SDC2). Similar findings were observed in UM cell lines and scRNA seq data from UM patient samples. BAP1 re-expression in UM cells reduced E-cadherin and CADM1 levels. Functionally, knockdown of E-cadherin decreased spheroid cluster formation and knockdown of CADM1 decreased growth of BAP1 mutant UM cells. Together, our findings demonstrate that BAP1 regulates the expression of CAMs which may regulate metastatic traits. Implications: BAP1 mutations and increased metastasis may be due to upregulation of cell adhesion molecules.