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.
During the last decades the therapeutics strategies for LUAD patients experienced a significant progress. The development of tailored therapies for a subset of LUAD patients bearing druggable oncogenic drivers (EGFR, BRAF, ALK, and ROS) together with immunotherapy with checkpoint inhibitors targeting PD-1/PD-L1 axis has shown to improve the survival of LUAD patients. In spite of these positive advances, a large subset of patients with LUAD accounting for approximately 20% of cases (10.000/year only in Italy) bear a spectrum of mutations whose drivers have not been targeted so far by any specific drug, do not respond to immunotherapy and are associated with particularly poor prognosis. Therefore, identifying therapeutic strategies for these exceptionally poor responders is of primary importance and represents a highly unmet clinical need. Our project aims at addressing how the oncogenic drivers (KEAP1/STK11) of this highly aggressive LUAD subtype are intertwined with lipid metabolism (in particular SCD1), ferroptosis and mitochondrial dynamics. A long-term prospect for this project will be to identify and characterize new therapeutically actionable pathways in highly aggressive LUAD. Our project wishes to provide the scientific community with a compendium of interrelated signals able to modulate LUAD progression. We aim to gain our knowledge of the signals emerging from oncogenic drivers and how they are related to physio-pathological events. Overall, the results arising from this research project may pave new ways toward the development of novel therapeutic therapies and precision medicine for aggressive LUAD, hopefully improving patient survival and decreasing therapy-related side effects.
Moreover, we can foresee that our project will impact on the following aspects: 1) In the ageing western societies cancer represents a tremendous social and economic burden and require that innovative therapeutic approaches are developed and implemented. Although this research proposal is limited up to a proof of principle stage, it will identify novel interconnected cancer signalling nodes with the potential to be carried further towards preclinical development. The outcomes of the project are expected to benefit a subset of lung cancer patients characterized by poor response to conventional, targeted or immuno-based therapy. 2) By combining top-class innovative approaches of signalling and cancer biology we will produce new knowledge on lipid metabolism and its intersection with mitochondrial functionality, ferroptosis and cell adaptation to stress. The information gained will constitute the proof of principle that will set a standard for future investigations. Moreover, by exploiting patenting of the best hits, we would also impact on the local economy, with potential spin offs that would further develop our novel targets.
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