Targeting fatty acid synthase suppresses tumor development in NF2/CDKN2A-deficient pleural mesothelioma

Abstract Pleural mesothelioma (PM) is an uncommon yet deadly cancer linked to asbestos exposure. The lack of effective early diagnosis and treatment leads to reduced life expectancy among patients with PM. This study aims to identify a novel molecular target inhibitor to develop more effective therapeutics for PM. Our drug screening assay showed that the fatty acid synthase (FASN) inhibitor cerulenin demonstrates strong and selective antiproliferative properties against NF2/CDKN2A(p16) -deficient PM cells, surpassing the effects of C75, cisplatin or pemetrexed. FASN protein is frequently detected in NF2/p16 -deficient PM tumor-derived tissues (15/15, 100%), but rarely in NF2/p16 -intact PM tumors (8/25, 32%). Notably, cerulenin administration successfully reduced the growth of NF2/p16 -deficient PM tumors in xenografted mice. Cerulenin inhibits mitochondrial fission by targeting dynamin-related protein 1 (DRP1) in NF2/p16 -deficient cells. Moreover, the disruption of the FASN gene leads to increased ubiquitination of DRP1. These findings suggest that FASN might play a role in the tumorigenesis of PM cells through the regulation of mitochondrial dynamics. This research offers a novel perspective on the potential development of precision medicine for PM.