Activating mutations in GNAQ/GNA11 occur in over 90% of uveal melanomas (UMs), the most lethal melanoma subtype; however, targeting these oncogenes has proven challenging and inhibiting their downstream effectors show limited clinical efficacy. Here, we performed genome-scale CRISPR screens along with computational analyses of cancer dependency and gene expression datasets to identify the inositol-metabolizing phosphatase INPP5A as a selective dependency in GNAQ/11-mutant UM cells in vitro and in vivo. Mutant cells intrinsically produce high levels of the second messenger inositol 1,4,5 trisphosphate (IP3) that accumulate upon suppression of INPP5A, resulting in hyperactivation of IP3-receptor signaling, increased cytosolic calcium and p53-dependent apoptosis. Finally, we show that GNAQ/11-mutant UM cells and patients’ tumors exhibit elevated levels of IP4, a biomarker of enhanced IP3 production; these high levels are abolished by GNAQ/11 inhibition and correlate with sensitivity to INPP5A depletion. Our findings uncover INPP5A as a synthetic lethal vulnerability and a potential therapeutic target for GNAQ/11-mutant-driven cancers.

GNAQ/GNA11的激活突变发生在超过 90% 的葡萄膜黑色素瘤 (UM) 中，这是最致命的黑色素瘤亚型；然而，事实证明，针对这些癌基因具有挑战性，并且抑制其下游效应子的临床疗效有限。在这里，我们进行了基因组规模的 CRISPR 筛选以及癌症依赖性和基因表达数据集的计算分析，以在体外和体内鉴定肌醇代谢磷酸酶 INPP5A 作为 GNAQ/11 突变 UM 细胞的选择性依赖性。突变细胞本质上产生高水平的第二信使肌醇 1,4,5 三磷酸 (IP3)，其在 INPP5A 抑制时积累，导致 IP3 受体信号传导过度激活、胞质钙增加和 p53 依赖性细胞凋亡。最后，我们发现 GNAQ/11 突变的 UM 细胞和患者的肿瘤表现出 IP4 水平升高，IP4 是 IP3 产生增强的生物标志物；这些高水平会被 GNAQ/11 抑制所消除，并与 INPP5A 耗竭的敏感性相关。我们的研究结果表明，INPP5A 是一种合成致命弱点，也是 GNAQ/11 突变驱动癌症的潜在治疗靶点。