Pyrimidine addiction: an Achilles’ heel of NF2-altered mesothelioma

Therapeutic options for patients with mesothelioma remain scarce and five-year survival is a meager ten percent. According to data from three large studies, 36% of mesotheliomas harbor neurofibromatosis 2 (NF2) mutations or loss ( https://bit.ly/4nGcRXk ; accessed on 06.30.2025), yet no targeted therapy exists for this molecular subtype of the disease. In the current issue of EMBO Molecular Medicine, Xu et al, demonstrate that NF2-deficiency of mesothelioma cells releases an NF2-mediated Hippo-pathway restraint, activates the Yes-associated protein (YAP)–carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD)/dihydroorotate dehydrogenase (DHODH) axis, and drives addiction to high-flux de novo pyrimidine biosynthesis (Xu et al, 2025). Moreover, the authors elegantly show that DHODH inhibitors elicit robust antitumor activity against NF2-altered mesothelioma and exhibit strong synergy with cisplatin, opening a new translational avenue for this tumor subtype.