Integrated Analyses of Multi-omic Data Derived from Paired Primary Lung Cancer and Brain Metastasis Reveals the Metabolic Vulnerability as a Novel Therapeutic Target

Duan, H.; Ren, J.; Wei, S.; Li, C.; Wang, Z.; Li, M.; Wei, Z.; Yang, Z.; Liu, Y.; Xie, Y.; Wu, S.; Hu, W.; Guo, C.; Zhang, X.; Liang, L.; Yu, C.; Mou, Y.; Jiang, Y.; Li, H.; Sugarman, E.; Deek, R. A.; Chen, Z.; Chen, L.; Chen, Y.; Yao, M.; Liu, L.; Zhang, G.

doi:10.1101/2024.01.02.573855

bioRxiv · 10.1101/2024.01.02.573855

Integrated Analyses of Multi-omic Data Derived from Paired Primary Lung Cancer and Brain Metastasis Reveals the Metabolic Vulnerability as a Novel Therapeutic Target

Duan, H.·Ren, J.·Wei, S.·Li, C.·Wang, Z.·Li, M.·Wei, Z.·Yang, Z.·Liu, Y.·Xie, Y.·Wu, S.·Hu, W.·Guo, C.·Zhang, X.·Liang, L.·Yu, C.·Mou, Y.·Jiang, Y.·Li, H.·Sugarman, E.·Deek, R. A.·Chen, Z.·Chen, L.·Chen, Y.·Yao, M.·Liu, L.·Zhang, G.

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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 deep understanding of 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 genomic, transcriptomic, proteomic and metabolomic data which were derived from a total number of 174 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. We uncovered that LC-BrMs exhibited significantly higher intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry and multiplexed immunofluorescence staining of patients paired tumor specimens. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids specific to LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.

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Duan, H., Ren, J., Wei, S., Li, C., Wang, Z., Li, M., Wei, Z., Yang, Z., Liu, Y., Xie, Y., Wu, S., Hu, W., Guo, C., Zhang, X., Liang, L., Yu, C., Mou, Y., Jiang, Y., Li, H., Sugarman, E., Deek, R. A., Chen, Z., Chen, L., Chen, Y., Yao, M., Liu, L., Zhang, G.. 2024-01-02. Integrated Analyses of Multi-omic Data Derived from Paired Primary Lung Cancer and Brain Metastasis Reveals the Metabolic Vulnerability as a Novel Therapeutic Target. https://doi.org/10.1101/2024.01.02.573855

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