ArticleNature cancer2024
INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11-mutant melanomas.
Article in Nature cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 14 citations in OpenAlex.
- Redox Homeostasis, Metabolic Pathways and Plasticity in Uveal Melanoma Compared to Other Cancers.Cancers · 2026Review
- Matched sampling reveals uncoupled phenotypic plasticity during metastasis formation in uveal melanoma.iScience · 2026Article
- Renaissance of farnesyltransferase inhibitors in cancer.Journal of translational medicine · 2026Review
- Shifting paradigms: phosphatases from basic biology to druggable targets.Biology open · 2026Article
- Article
- Chromosome 3p deletion leads to extensive genomic alterations in diverse cancers and confers synthetic lethality in uveal melanoma.bioRxiv : the preprint server for biology · 2026Article
- Identification of cancer mini-drivers by deciphering selective landscape in the cancer genome.Briefings in bioinformatics · 2026Article
- Integrative discovery and targeted proteomics elucidate the plasma exosomal landscape in thyroid disorders, with emphasis on papillary thyroid carcinoma complicating Hashimoto's thyroiditis.Frontiers in endocrinology · 2026Article
- ITPKA promotes invasive phenotypes in clear cell renal cell carcinoma through functional modulation of PPAR signaling.American journal of cancer research · 2026Article
- Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer.iScience · 2025Article
- Oxidative stress-related genes in uveal melanoma: the role of CALM1 in modulating oxidative stress and apoptosis and its prognostic significance.Frontiers in oncology · 2025Article
- Going Rogue: Mechanisms, Regulation, and Roles of Mutationally Activated GMolecular pharmacology · 2024Review
- The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte proliferation and senescence.Science signaling · 2024Review
- Sturge-Weber syndrome: updates in translational neurology.Frontiers in neurology · 2024Review
Corrections and comments
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Authors and funding
22 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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