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Updated: Jul 5, 2025
Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
Published on: May 30, 2025
INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11-mutant melanomas
Ahmed M O Elbatsh1, Ali Amin-Mansour2, Anne Haberkorn1
1Oncology, Novartis Institute for Biomedical Research, Basel, Switzerland.
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.
Insights
Researchers identified INPP5A as a key vulnerability in GNAQ/11-mutant uveal melanoma (UM). Suppressing INPP5A triggers apoptosis in UM cells, offering a potential new therapeutic target for this lethal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating mutations in GNAQ/GNA11 drive over 90% of uveal melanomas (UMs), the deadliest melanoma subtype.
- Targeting these oncogenes directly has been difficult, and downstream effector inhibition shows limited clinical success.
Purpose of the Study:
- To identify novel therapeutic targets for GNAQ/11-mutant uveal melanoma.
- To investigate the role of INPP5A in GNAQ/11-driven cancers.
Main Methods:
- Genome-scale CRISPR screens were employed to identify cancer dependencies.
- Computational analyses of cancer dependency and gene expression datasets were performed.
- In vitro and in vivo studies assessed the impact of INPP5A suppression in GNAQ/11-mutant UM cells.
Main Results:
- INPP5A was identified as a selective dependency in GNAQ/11-mutant UM cells.
- INPP5A suppression led to inositol 1,4,5 trisphosphate (IP3) accumulation, hyperactivated IP3-receptor signaling, increased cytosolic calcium, and p53-dependent apoptosis.
- Elevated inositol 1,4,5,6-tetrakisphosphate (IP4) levels in GNAQ/11-mutant UM cells and tumors correlated with INPP5A depletion sensitivity.
Conclusions:
- INPP5A is a synthetic lethal vulnerability in GNAQ/11-mutant uveal melanoma.
- INPP5A represents a promising therapeutic target for GNAQ/11-mutant cancers.
- IP4 can serve as a biomarker for enhanced IP3 production in GNAQ/11-mutant UM.
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