INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11 mutant uveal melanoma

Uveal melanoma (UM) is a lethal disease in which half of all patients develop metastasis and die within one year following metastasis tumor diagnosis, underscoring the urgent need for effective therapies. Activating mutations in GNAQ/GNA11, encoding Gq proteins, are the oncogenic drivers for over 90 percent of UMs, however, agents targeting GNAQ/11 effectors have shown limited clinical efficacy. Here, we combined CRISPR screens with analyses of large-scale cancer dependency and mRNA expression datasets and identified the phosphatase INPP5A as a selective dependency for GNAQ/11-mutant cells in vitro and in vivo. Upon INPP5A depletion, the mutant cells accumulate high levels of inositol trisphosphate (IP3) resulting in hyperactivated IP3/IP3-receptor signaling, increased cytosolic calcium and apoptosis, while suppressing the elevated IP3 levels or co-depleting the receptor alleviated this dependency. We find that IP4 is a biomarker of enhanced IP3 production that correlates with sensitivity to INPP5A depletion and is elevated in GNAQ/11-mutant uveal melanoma cells and patients tumors. Our findings indicate that INPP5A is a synthetic lethal vulnerability and promising therapeutic target for GNAQ11-mutant-driven tumors.