ATR is a critical dependency gene for uveal melanoma
ATR is a critical dependency gene for uveal melanoma.
GNAQ, GNA11, CYSLTR2, and PLCB4 are well-characterized oncogenic drivers of uveal melanoma. The oncogenic stress induced by these mutations creates a reliance on specific dependency genes that support tumor cell proliferation and survival. Using the Dependency Map (DepMap), ATR was identified as a key regulator of uveal melanoma cell fitness. Pharmacologic inhibition of ATR with the selective inhibitor VE‑822 in 92.1, MEL270 and MP38 cells (low‑risk, intermediate‑risk and high‑risk models) led to DNA double‑strand break formation, micronuclei accumulation and a marked reduction in colony and spheroid formation. Transcriptomic profiling revealed that successful completion of S‑phase and mitotic progression are critical determinants of the response to ATR inhibition. Combining ATR inhibition with paclitaxel or microtubule inhibition produced significant synergy in the models. These findings identify ATR as a potential therapeutic vulnerability in uveal melanoma.
The study demonstrates that ATR inhibition compromises the proliferation of uveal melanoma cells and triggers DNA damage response pathways, indicating ATR as a vulnerability that could be targeted with existing inhibitors such as VE‑822 and standard chemotherapies like paclitaxel.
Bizonyítékszint: Számítógépes vagy elméleti. Modellből vagy adatbányászatból származó jel.
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