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(Abstract)

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This article discusses a study on malignant pleural mesothelioma (MPM), a rare and aggressive thoracic malignancy. The study focuses on the role of the tumor suppressor gene neurofibromatosis type 2 (NF2) in MPM and its potential as a therapeutic target. Using CRISPR-Cas9 gene-editing technology, the researchers generated NF2-knockout MPM cell lines and conducted comprehensive genomic and metabolic analyses. They found that NF2 inactivation promotes the aggressive nature of MPM and is associated with unfavorable clinical outcomes.<br /><br />The study identified the adaptive reprogramming of de novo pyrimidine synthesis, a metabolic pathway, as a major molecular alteration in NF2-deficient MPM. This reprogramming is triggered by the constitutive activation of a protein called YAP1. The researchers also found that blocking de novo pyrimidine synthesis selectively kills NF2-deficient tumor cells through nucleotide pool imbalance, DNA damage, and apoptosis.<br /><br />Overall, this study highlights de novo pyrimidine synthesis as a metabolic vulnerability driven by NF2 inactivation in MPM. It suggests that targeting this pathway could be a tumor-selective therapeutic strategy for NF2-mutant MPM. This research provides important insights into the underlying biology of MPM and offers potential avenues for developing targeted therapies for this aggressive malignancy.

Asset Subtitle

Duo Xu

Meta Tag

Speaker Duo Xu

Topic Mesothelioma, Thymoma & Other Thoracic Tumors: Translational

Keywords

malignant pleural mesothelioma

tumor suppressor gene

NF2

CRISPR-Cas9

genomic analysis

metabolic analysis

pyrimidine synthesis

YAP1 protein

targeted therapies

aggressive malignancy