Abstract 4160: Lipid metabolism is a metabolic vulnerability in LKB1 mutant, KRAS driven non-small cell lung cancer

Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers worldwide, with KRAS-driven NSCLC representing 30% of these cases. The introduction of immunotherapy has improved outcomes in advanced lung cancer, however, many patients with lung cancer do not respond to this treatment, and some develop severe side effects. Patients with KRAS-driven NSCLC harbouring a co-mutation in the LKB1 gene (KL), have a significantly poorer response to immunotherapy compared to patients harbouring a KRAS and TP53 co-mutation (KP). However, the reason for this difference in response to immunotherapy is largely unknown. Recent studies demonstrate that metabolic vulnerabilities in KL genotypes can influence therapeutic response. Our research aims to identify and target these vulnerabilities in KL NSCLC, with the aim to enhance response to immunotherapy. Moreover, we will focus on creating a novel three-dimensional (3D) NSCLC co-culture model to study immunotherapy response. Using the cBioPortal mRNA database and publicly available patient protein data, we completed a bioinformatic analysis of key genes, proteins, and metabolites in major metabolic pathways. Notably, lipid metabolism pathways displayed significant differences between KP and KL genotypes, specifically the beta-oxidation of fatty acids and fatty acid synthesis pathways. Proteins involved in the beta-oxidation pathway showed significant upregulation in KL patients such as Acetyl-CoA Acetyltransferase 1, Acyl-CoA Dehydrogenase, Hydroxyacyl-CoA Dehydrogenase and Enoyl-CoA Hydratase, and proteins involved in fatty acid synthesis also displayed upregulation in KL patients. We conducted a drug screen using a series of inhibitors targeting proteins in the fatty acid synthesis and beta oxidation pathway, and observed strong efficacy in KL NSCLC cell lines. Moreover, we observed a reduction in cell migration, colony formation and 3D spheroid formation in response to fatty acid synthesis inhibitors in KL NSCLC. Separately, we have successfully established 3D co-culture models of NSCLC cell lines and human T-cells isolated from patient samples. We found the optimum NSCLC cell number to be 50,000 cells per gel. Using immunohistochemistry, we also observed positive Ki67 staining confirming cell proliferation within the cultures and low cleaved-caspase 3 staining indicating minimal cell death. In conclusion, we have identified fatty acid synthesis as a potential metabolic vulnerability in KL NSCLC, and targeting this pathway could be a potential therapeutic option for patients with this genotype of NSCLC. Further analysis, supported by our novel 3D co-culture model, aims to analyse the consequences of targeting this specific pathway in combination with immunotherapy in the KL genotype of NSCLC. Citation Format: Saoirse Flanagan, Robyn Stanley, Beatrice Malacrida, David O’Reilly, Jarushka Naidoo, Paul Murray, Catríona M. Dowling. Lipid metabolism is a metabolic vulnerability in LKB1 mutant, KRAS driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4160.