Ricerc@Sapienza

Lung cancer is the leading cause of cancer mortality. Although in recent years significant clinical advances has been made due to immunotherapy and targeted therapies, there are subset of patients who harbor undruggable mutations (KEAP1 and/or STK11) conferring immunotherapy resistance and poor prognosis. Notably, both KEAP1 and STK11 control pivotal signalling cascades which ultimately impact cell metabolism, antioxidant defense and cell energy production. The importance of metabolic reprogramming in this highly aggressive LUAD has been further emphasized by the observation that the fitness of STK11-KEAP1 mutated tumours depends on the lipid desaturation enzyme SCD1.
This project has been designed to elucidate the pivotal role of lipid and mitochondrial metabolism in the development of the most aggressive forms of LUAD. In particular, it will be evaluated the impact of SCD1 on the establishment of an aggressive phenotype and the lack of responsiveness to immunotherapy of STK11/KEAP1 mutated tumours. A biological process to which particular emphasis will be given is that of ferroptosis. An established collection of LUAD patient-derived and stable cell lines representative of different mutational profiles will be used to assess the contribution of SCD1 in more aggressive tumours. Genomic and transcriptomic analyses will be performed to correlate the mutational patterns with dysregulation of lipid metabolism. Drug sensitivity assays and mechanistic studies will be carried out to validate the concept of co-targeting negative regulators of ferroptosis in conjunction with SCD1 inhibitors is a valid approach for defeat LUAD cells fitness. Finally, the composition of the secretome of 2D and 3D cells will be determined to establish a correlation between the secretion of immune-evasive cytokines/chemokines and a particular combination of mutations.