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INPP5A磷酸酶是GNAQ和gna11突变型黑色素瘤的合成致死靶点

原文发布日期：2024-01-17

英文摘要：

摘要翻译：

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文章：

INPP5A磷酸酶是GNAQ和gna11突变型黑色素瘤的合成致死靶点

INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11-mutant melanomas

原文发布日期：2024-01-17

英文摘要：

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.

摘要翻译：

激活突变发生在角膜黑素细胞癌（UMs）中，占所有UM的90%以上，尤其是最致命的UM亚型；然而，针对这些原发灶靶向治疗一直十分困难，并且抑制它们下游效应器的临床效果有限。我们进行了大规模CRISPR筛选以及癌症依赖性和基因表达数据的计算分析，从而在体内外将INPP5A（一种对GNAQ/11突变细胞系具有选择性依赖性的转运酶）识别为一种潜在的治疗靶点。突变细胞自身会产生高水平的第二信使甘油三酯（IP3），当INPP5A被抑制时，这些IP3会积累，导致超活化IP3受体信号通路、胞内钙离子浓度升高以及p53介导的程序性死亡增强。最后我们发现，GNAQ/11突变细胞系和患者肿瘤中存在高IP4（一种增强IP3产生的标志物），这种高度IP4水平被GNAQ/11抑制剂所降低，并且与INPP5A缺乏相关联，并且对INPP5A脱氧有关。我们的发现揭示了INPP5A作为一种合成性致命的脆弱点，可能为驱动GNAQ/11突变的癌症提供潜在的治疗靶点。