JS06.4.A MULTI-OMIC CHARACTERIZATION OF LUNG CANCER BRAIN METASTASIS REVEALS THE METABOLIC VULNERABILITY AS A NOVEL THERAPEUTIC TARGET

Abstract

Abstract Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A better understanding of the molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Here, we performed integrated analyses of both bulk and single cell genomic transcriptomic and proteomic data derived from five published and two newly generated patient cohorts, totaling 141 patients with paired and unpaired primary lung cancer and LC-BrM. This was subsequently validated by immunohistochemistry (IHC) and multiplexed immunofluorescence (mIF) staining. LC-BrMs exhibited significantly lower tumor mutational burden but higher intra-tumor heterogeneity. We observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TP53, MUC16, LRP1B, KRAS, FAT3, and NF1. In addition, the genome-wide landscape of somatic copy number alterations (SCNAs) was found to be similar between primary lung cancers and LC-BrM lesions. Nevertheless, three regions of focal amplification were significantly enriched in LC-BrMs, including 11q13.1, 14q11.2, and 12p13.31. Integrated analyses of transcriptional and proteomic data revealed mitochondrial-specific metabolism was activated in LC-BrMs and accompanied by a suppressed tumor immune microenvironment, which was further corroborated by IHC and mIF data. Importantly, targeting oxidative phosphorylation with gamitrinib in combination with anti-PD1 immune checkpoint blockade (ICB) therapy significantly improved the survival of mice with LC-BrMs. In conclusion, our findings not only provide comprehensive and multi-omic perspectives of the molecular mechanisms of LC-BrMs but also contribute to the development of potential therapeutic strategies with the goal of translating it into clinical trials for patients with LC-BrMs.