顺铂（CDDP）是晚期头颈鳞状细胞癌（HNSCC）的主要治疗方法，尽管其内在性和获得性抗性频率较高。我们假设肿瘤通过代谢重构的增强还原状态获得了CDDP耐药性。为了验证这个模型并了解适应性代谢方案的印记方式，我们通过全外显子测序，RNA-seq，质谱法，定态和代谢流分析，对来自多个基因组背景的CDDP耐药HNSCC克隆进行了综合分析。 KEAP1失活突变或KEAP1 RNA减少与CDDP耐药细胞中的Nrf2激活相关，这在功能上导致耐药性。蛋白质组学确定了下游Nrf2目标的升高和参与生物质和还原当量生成，葡萄糖，谷胱甘肽，NAD（P）和羰基酸代谢的酶的富集。这伴随着生化和代谢证据的增强还原状态，该状态依赖于协调的葡萄糖和谷氨酰胺分解，与能量产生和增殖减少有关，尽管线粒体结构和功能正常。我们的分析确定了与CDDP耐药有关的协调代谢变化，这可能通过靶向这些汇合途径提供新的治疗方法。 ©2023。作者（们）在Springer Nature Limited独家许可下发布。

Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring.To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics.Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function.Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.