1. Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.
- Author
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Yu W, Chen Y, Putluri N, Osman A, Coarfa C, Putluri V, Kamal AHM, Asmussen JK, Katsonis P, Myers JN, Lai SY, Lu W, Stephan CC, Powell RT, Johnson FM, Skinner HD, Kazi J, Ahmed KM, Hu L, Threet A, Meyer MD, Bankson JA, Wang T, Davis J, Parker KR, Harris MA, Baek ML, Echeverria GV, Qi X, Wang J, Frederick AI, Walsh AJ, Lichtarge O, Frederick MJ, and Sandulache VC
- Subjects
- Humans, Cisplatin metabolism, Squamous Cell Carcinoma of Head and Neck, Kelch-Like ECH-Associated Protein 1 genetics, NF-E2-Related Factor 2 genetics, Drug Resistance, Neoplasm genetics, Cell Line, Tumor, Glucose, Head and Neck Neoplasms, Antineoplastic Agents pharmacology
- Abstract
Background: 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., Methods: 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., Results: 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., Conclusions: 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.)
- Published
- 2023
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