Impact of small molecule‐mediated inhibition of ammonia detoxification on lung malignancies and liver metabolism

Abstract

Metabolically induced cancer heterogeneity creates a largesourceofnovelpotentialtargetstowardsanenhancedther-apeutic window alone and in combination with classicchemo-andradiotherapy[1,2 ].Thisisofparticularinterestfor non-small cell lung cancer (NSCLC), which accountsfor more than 80% of all lung tumor types characterizedby limited responses to current treatment options [3–5].Genetically-definedKRAS/LKB1-mutant NSCLC tumorsexploit the proximal urea cycle enzyme carbamoyl phos-phate synthetase 1 (CPS1) as an intermediate step forpyrimidine biosynthesis, thereby contrasting its crucialhepatic role in ammonia detoxification [6–8]. Thus, CPS1could serve as a novel target for NSCLC susceptibility(Figure1A). In this study, we investigated the metabolicchanges observed in both NSCLC and healthy hepaticsystems following the identification, characterization andapplication of a small molecule inhibitor of ectopic CPS1functionality.