Abstract LB057: Metabolic vulnerabilities in non-small cell lung cancer metastasis

Abstract Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, largely due to its propensity to metastasize to distant organs. To identify new treatment strategies, there is a need to better understand the biological factors, such as metabolic reprogramming, that enable the survival of NSCLC cells throughout the metastatic cascade. However, standard cell culture media have non-physiological levels of key nutrients, limiting the ability to translate these findings in vivo. Here, we integrated physiological in-vitro and in-vivo approaches to reveal how metabolic plasticity drives NSCLC progression. Culturing NSCLC cells in a Human-Plasma-Like Medium versus conventional culture media revealed a marked reduction in glucose- and glutamine-derived carbon oxidation in the tricarboxylic acid (TCA) cycle. Next, we utilized non-adherent conditions to mimic extracellular matrix detachment and circulating tumor cells. We identified that NSCLC cells increased their reliance on lactate import and contribution to TCA cycle intermediates, demonstrating both a capacity to shift fuel sources under selective pressure and the influence of physiological nutrient environments on cancer cells. To assess how metabolic reprogramming supports NSCLC progression in-vivo, we utilized patient-derived xenografts with novel capacity for spontaneous metastasis. Inhibition of lactate import significantly reduced metastatic spread without substantially affecting primary tumor growth, suggesting a shift to lactate reliance in metastatic NSCLC cells. Together, these data suggest that circulating NSCLC cells' survival relies on metabolic flexibility, with key alterations of nutrient contribution to the TCA cycle. These data underscore the therapeutic potential of targeting metabolic dependencies to hinder NSCLC progression. Citation Format: Mayher Kaur, Massar Alsamraae, Nia G. Hammond, Robert Cameron, Brianna Chang, Brandon Faubert. Metabolic vulnerabilities in non-small cell lung cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB057.