ATR Is a Critical Dependency Gene Supporting Uveal Melanoma Cell Survival

GNAQ, GNA11, CYSLTR2, and PLCB4 are well-characterized oncogenic drivers of uveal melanoma (UM). The oncogenic stress induced by these mutations creates a reliance on specific dependency genes that support tumor cell proliferation and survival. However, the genes that broadly contribute to UM cell fitness remain incompletely defined. Using the Dependency Map (DepMap) and Sanger Cancer Dependency bioinformatic resources, we identified ATR (HGNC:882; ATR checkpoint kinase) as a key regulator of UM cell fitness. Pharmacologic inhibition of ATR with the selective inhibitor VE-822 in 92.1 and MP38 cells, established models of low-risk and high-risk UM respectively, resulted in DNA double-strand break formation, micronuclei accumulation, and a marked reduction in cell viability. RNA sequencing followed by pathway enrichment analysis was performed to characterize the transcriptional response to ATR inhibition. Transcriptomic profiles from both cell lines support the hypothesis that successful completion of S phase and mitotic progression are critical determinants of survival following ATR inhibition. Further support for the hypothesis that mitotic progression is key to survival for ATR inhibited cells was obtained by treating with VE-822, paclitaxel, or the combination. Combined ATR and microtubule inhibition produced significant synergistic cytotoxicity in both UM models. Collectively, these findings identify ATR as a potential therapeutic vulnerability in uveal melanoma.