Abstract 6042: Targeting metabolic vulnerabilities in MET-driven lung cancer brain metastases

Abstract Non-small cell lung cancer (NSCLC) has the highest incidence of brain metastases (BM) with almost 40% of lung cancer patients developing BM throughout the course of their disease. The presence of BM portends an extremely poor prognosis even when extracranial disease is controlled and remains a major clinical problem. To date, there are no BM-specific targeted therapies available. MET is a receptor tyrosine kinase that, upon binding hepatocyte growth factor (HGF), mediates proliferation, epithelial-mesenchymal transition, invasion, angiogenesis and metastasis. The MET pathway has emerged as a targetable oncogenic driver of NSCLC BM; however, almost half of patients with MET alterations fail to respond to MET tyrosine kinase inhibitors (TKIs). Interestingly, we identified a significant enrichment of MET amplification in lung adenocarcinoma (LUAD) BM (16%) compared to primary LUAD (3%) or liver metastases (5%). Subsequent RNA-sequencing and Gene Set Enrichment Analysis of MET-amplified and non-MET amplified LUAD BM identified many dysregulated pathways including those involved in cellular metabolism. In contrast to previous reports in melanoma which found that oxidative phosphorylation was the dominant metabolic pathway in BM, we found that genes involved in glycolysis and glutamine catabolism were increased in the high MET expressing cell lines compared to low MET expressing cell lines. We confirmed glycolytic pathway up-regulation by evaluating the activity of hexokinase 1 and 2 (HK1, HK2), glutaminase (GLS), and lactate dehydrogenase (LDHA) in a MET-amplified metastatic line (H1993) compared to a MET wild-type NSCLC cell line (H2073) derived from the same patient. Further, bioenergetic analysis revealed that H1993 cells were more metabolically active, generated higher levels of ATP, and exhibited increased glycolysis compared to H2073 cells. The enhanced metabolic activity of H1993 cells increased their susceptibility to glucose deprivation and metabolic inhibitors, supporting that metabolic reprogramming is important for MET-driven disease. Additionally, untargeted metabolomics of MET amplified compared to non-MET amplified cells identified alterations in numerous amino acid catabolism pathways, including glutathione biosynthesis among other novel pathways. Treatment with the MET TKI capmatinib similarly reduced glycolysis-associated gene expression, oxygen consumption, extracellular acidification, and amino acid catabolism generating a metabolic phenotype more comparable to non-MET amplified NSCLC. Together, our data show MET-amplified NSCLC BM undergo metabolic reprogramming, which can be inhibited to suppress tumor growth. Current and future experiments are exploring whether we can specifically target MET altered BM with glycolytic inhibitors. Citation Format: Kasey R. Cargill, Sanja Dacic, Riyue Bao, Bharathri Sivakama, Eric S. Goetzman, Steven J. Mullett, Stacy G. Wendell, Sameer Agnihotri, Laura P. Stabile, Timothy F. Burns. Targeting metabolic vulnerabilities in MET-driven lung cancer brain metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6042.