ATR is a critical dependency gene for uveal melanoma

Abstract

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), 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, MEL270 and MP38 cells, established models of low-risk, intermediate-risk, and high-risk UM respectively, resulted in DNA double-strand break formation, micronuclei accumulation, and a marked reduction in colony and spheroid formation. RNA sequencing followed by pathway enrichment analysis was performed to characterize the transcriptional response to ATR inhibition. Transcriptomic profiles from cell lines support the hypothesis that successful completion of S phase and mitotic progression are critical determinants of the response of UM cells to ATR inhibition. Further support for the hypothesis that mitotic progression is a key factor for ATR-inhibited cells was obtained by treating with VE-822, paclitaxel, or the combination. Combining ATR and microtubule inhibition produced significant synergy in the UM models. Collectively, these findings identify ATR as a potential therapeutic vulnerability in uveal melanoma.