2023 World Conference on Lung Cancer (Posters)-P2.21. Mutant NF2-Driven De Novo Pyrimidine Synthesis is a Metabolic Vulnerability in Malignant Pleural Mesothelioma

P2.21. Mutant NF2-Driven De Novo Pyrimidine Synthesis is a Metabolic Vulnerability in Malignant Pleural Mesothelioma - PDF(Slides)

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Researchers have identified a metabolic vulnerability in malignant pleural mesothelioma (MPM) driven by mutant NF2 gene. MPM is a lethal cancer caused by the inactivation of tumor suppressor genes. However, the molecular basis of metabolic dysfunction in MPM is not well understood. The study found that MPM exhibits a dysregulated metabolic profile, and NF2 is a mutated gene specific to the metabolic subtype of MPM. The loss of NF2 leads to rewiring of de novo pyrimidine synthesis, which is a metabolic vulnerability in MPM. The study used genome-edited cell models and conducted RNA-Seq, metabolomics, and proteomics analyses to validate their findings. They observed elevated de novo pyrimidine synthesis in NF2-deficient MPM cells, and further in vitro and in vivo studies confirmed the essential dependency on this pathway for rapid cell proliferation in NF2-driven MPM tumorigenesis. <br /><br />The study highlights the presence of metabolic dysregulation and heterogeneity in MPM. The researchers suggest that targeting the de novo pyrimidine synthesis pathway could be a potential therapeutic strategy for NF2-driven MPM. The findings provide insights into the molecular mechanisms underlying MPM and open avenues for further research and development of targeted therapies. However, more studies, including patient-derived evidence, are needed to fully understand the clinical implications of targeting this metabolic vulnerability.

Asset Subtitle

Duo Xu

Meta Tag

Speaker Duo Xu

Topic Mesothelioma, Thymoma & Other Thoracic Tumors: Translational

Keywords

metabolic vulnerability

malignant pleural mesothelioma

NF2 gene

tumor suppressor genes

metabolic dysfunction

de novo pyrimidine synthesis

genome-edited cell models

rapid cell proliferation

metabolic dysregulation

targeted therapies