Abstract 860: Identifying mechanisms associated with slow proliferation of BAP1 mutant uveal melanoma cells

Abstract Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Primary tumors in the uveal tract are often treated successfully by enucleation or radiotherapy but 50% of cases develop metastases which occur primarily in the liver. Patients diagnosed with metastatic UM usually have a poor prognosis with a short median survival of 5-18 months due to the lack of effective treatment options. Metastatic UM responds poorly to many therapeutic options. Inactivating mutations in BRCA1-associated protein 1 (BAP1), a tumor suppressor gene and de-ubiquitinating (DUB) enzyme, have been reported in >80% metastasizing UM and thus are associated with elevated risks of UM metastasis. However, the role of BAP1 in UM metastasis is unclear. Interestingly, silencing of BAP1 in UM cell lines was shown to inhibit UM cell proliferation and cell cycle progression. Consistent with this finding, we show that BAP1-deficient or BAP1 mutant UM cells proliferated slower than BAP1 wild-type (WT) cell lines. Re-expression of BAP1 in a BAP1-deficient or mutant UM cell line, MP65, also increased the proliferation rate of cells. Analysis of reverse phase protein array (RPPA) identified that phosphorylation of the S6 ribosomal protein is elevated in BAP1 proficient cells. Re-expression of BAP1 WT also increased phosphorylation of S6 and its upstream regulator, p70S6K1. Additionally, BAP1 mutant UM cells were more viable compared to isogenic cells expressing BAP1 WT in response to amino acid deprivation. These findings suggest that loss of BAP1 is associated with better survival under environmental stress, a critical step during metastasis. Positivity for pS6 was detected in all metastatic UM specimen tested regardless of BAP1 status. This suggests a role of the tumor microenvironment in regulating pS6 levels in UM cells at the metastatic site. Our findings show BAP1-dependent regulation of UM cell proliferation and response to stress, and uncover S6 and its associated pathway as an opportunity for therapeutic target in BAP1 mutant UM. Citation Format: Vivian Chua, Usman Baqai, Timothy J. Purwin, Angela Jeon, Anna Han, Andrew Aplin. Identifying mechanisms associated with slow proliferation of BAP1 mutant uveal melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 860.