Synthetic lethal screens reveal p300/CBP as a vulnerability for GNAQ-driven uveal melanomas

Abstract Uveal melanoma is the most common intraocular cancer in adults, driven by activating mutations in GNAQ or GNA11 , which encode the G proteins Gαq and Gα11. Currently, therapeutic options for uveal melanoma, particularly metastatic uveal melanoma, remain limited. Through an isogenic CRISPR screening approach, we identify EP300 , which encodes the protein lysine acetyltransferase p300, as a top synthetic lethal vulnerability in the context of GNAQ mutation. Notably, CREBBP , which encodes the closely related paralogue CBP, also emerges among the top-ranked candidates. Mechanistically, we find that p300 and CBP support YAP-dependent transcription downstream of oncogenic Gαq in uveal melanoma through interactions with YAP at chromatin. These interactions enhance H3K27 acetylation at the promoters and putative enhancers of YAP target genes and promote the recruitment of RNA polymerase II and CDK9. Using multiple in vivo models representing clinically relevant stages of Gαq-mutant uveal melanoma, we find that p300 inhibition, by both genetic and pharmacological approaches, profoundly impairs tumor growth and metastasis. Taken together, this study establishes p300 as a potential therapeutic target for Gαq-driven uveal melanoma, which is dependent on unrestrained YAP signaling.