Abstract 1797: Investigating the significance of OXPHOS activity in non-small cell lung cancer brain metastases

Abstract

Abstract Background: Brain metastasis is a common and devastating occurrence for patients with non-small cell lung cancer (NSCLC). NSCLC patients with brain metastases have a poor median overall survival of 2-3 months, highlighting the urgency for novel treatment strategies. One approach to understanding and potentially targeting metastasis is via cancer metabolism. During the metastatic cascade, cancer cells must survive and adapt to the differential nutrient environments they encounter, including the brain. The blood brain barrier limits the availability of many metabolites, leading metastatic cells to alter their nutrient use to survive. RNA sequencing analyses of NSCLC brain metastases suggest that increased oxidative phosphorylation (OXPHOS) may be one such metabolic adaptation in the brain. The aim of this study was to determine the necessity of OXPHOS activity as a metabolic adaptation for NSCLC cells to proliferate in the unique metabolic environment of the brain. Materials and Methods: NSCLC cells were cultured in media mimicking the metabolic environments of the brain and blood. Expression of mitochondrial markers were evaluated by immunoblot in cells cultured across media conditions. The effects of the OXPHOS inhibitor IACS-010759 were assessed by cell growth as well as stable isotope tracing with [U-13C] glucose. Patient derived xenografts (PDXs) were derived from a cohort of patients with NSCLC who underwent stable isotope tracing with [U-13C] glucose. Mice bearing subcutaneously implanted PDXs were treated daily with 5mg/kg IACS-010759 and metastatic burden was measured by flow cytometry and histology. Results: Tracing studies in patients revealed that high enrichment in OXPHOS-related metabolites in the primary tumor correlated with worse patient outcomes. Compared with other media conditions, cells cultured in media replicating the metabolic environment of the brain have increased expression of mitochondrial proteins, increased 13C glucose labeling in the TCA cycle, and a larger reduction in proliferation with IACS-010759 treatment. Using our PDX models, inhibition of OXPHOS with IACS-010759 had little effect on subcutaneous tumor growth but reduced metastasis in the lung and the brain. Conclusions: OXPHOS activity may be enhanced in NSCLC brain metastases due to the unique metabolic environment of the brain. This elevated OXPHOS activity may be necessary for NSCLC brain metastasis growth, as OXPHOS inhibition reduced metastasis in the brain. NSCLC cells may undergo mitochondrial biogenesis to support survival in this unique metabolic environment, and this may represent an area of therapeutic vulnerability for brain metastases. Citation Format: Nia G. Hammond, Massar Alsamraae, Mayher Kaur, Rachel Zuckerman, Brianna Chang, Robert Cameron, Aaron Dyas, Brandon Faubert. Investigating the significance of OXPHOS activity in non-small cell lung cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1797.