A22 Integrated Proteometabolomic Analysis Reveals Metabolic Vulnerabilities in Small-Cell Lung Cancer
Journal of Thoracic Oncology(2020)
摘要
Small-cell lung cancer (SCLC) is the third most common histology of lung cancers and is extremely aggressive and highly metastatic. Although SCLC responds well to radiation and standard platinum-based chemotherapy, this is nearly invariably followed by relapse and the emergence of chemoresistant disease. Hence, SCLC has been declared a recalcitrant malignancy by the NCI, and there is an urgent need to identify new and actionable therapeutic vulnerabilities for treatment-naïve and chemoresistant SCLC. To this end we performed unbiased activity-based (ATP-binding) proteome profiling (ABPP), expression proteomics, and untargeted metabolomics on a panel of SCLC and NSCLC cell lines, patient-derived lung tumor tissues, and PDX including paired treatment-naïve and cisplatin-resistant SCLC. These studies revealed highly elevated activity of enzymes associated with glycolysis, lipid biosynthesis, and purine metabolism in SCLC. In addition, metabolomic analysis identified concordant upregulation of metabolites in these pathways in SCLC. We further performed screening with available metabolic drugs on SCLC and NSCLC cell lines. The results showed that the MCT1/MCT2 lactate transport inhibitor SR-13800 and the PFKFB3 inhibitors 3PO and PFK15 compromised SCLC cell growth and their combined inhibition showed synergy, provoking rapid SCLC cell death. Flux, metabolomic, and genetic (CRISPR-editing) analysis of SCLC cells revealed that MCT1/2 inhibition loss blocked glycolysis and provoked a shift towards oxidative phosphorylation (OXPHOS), and that this provoked increases in intracellular lactate and dihydroxyacetone phosphate (DHAP) and a marked shift in the NAD+ to NADH ratio towards NADH. In addition, levels of amino acids that can generate NAD+ were also significantly reduced. In contrast and surprisingly, PFKFB3 inhibition led to a collapse in OXPHOS and provoked increases in glycolysis and increased efflux of lactate. The combined inhibition of MCT1/2 and PFKFB3 amplified the metabolic deficits provoked by MCT1/2 and led to metabolic collapse via suppression of both glycolysis and OXPHOS. Thus, cotargeting MCT1/2 and PFKFB3 provokes synthetic lethality in SCLC, supporting the notion that their dual inhibition will be an effective treatment strategy for this lethal malignancy.
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关键词
lung cancer,metabolic vulnerabilities,small-cell
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