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

[摘要] Metabolically induced cancer heterogeneity creates a largesource of novel potential targets towards an enhanced therapeutic window alone and in combination with classicchemo- and radiotherapy [1, 2]. This is of particular interestfor 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-defined KRAS/LKB1-mutant NSCLC tumorsexploit the proximal urea cycle enzyme carbamoyl phosphate 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(Figure 1A). 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.

[学科分类] 社会科学、人文和艺术（综合）