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.
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This work was supported by the National Institute of Dental and Craniofacial Research through R03DE028858 and the National Cancer Institute through U54CA274321. VCS, SYL, YC and JAB were supported by the Cancer Prevention and Research Institute of Texas (CPRIT) grant RP170366. NP is supported by the CPRIT Proteomics and Metabolomics Core Facility (RP210227), NIH (P30 CA125123 R01CA220297, R01CA216426, P42ES027725) and Dan L. Duncan Cancer Center. This work was supported by the National Institutes of Health (AG068214-01, AG061105, GM066099, and AG074009 to OL). JA was supported by a training fellowship from the Gulf Coast Consortia, on the NLM Training Program in Biomedical Informatics & Data Science (T15LM007093). Work performed through the Mouse Metabolism and Phenotyping Core (Seahorse) is supported by NIH UM1HG006348 and NIH R01DK114356 and flowing NIH grant P30ES030285 (CW) GVE is a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research. GVE is supported by CPRIT RR200009; NIH 1K22CA241113-01, and a Breast Cancer Alliance Young Investigator Grant. AJW is supported by CPRIT GCC Combinatorial Drug Discovery Program (RP200668) and NIH NIGMS (R35GM142990). CC is partially supported by CPRIT (RP210227 and RP200504), and NIH P30ES030285 and P42 ES0327725 grants. CS and RTP are supported by CRPIT CFSA core grants RP150578 and RP200668. XQ is supported by NIH R43-GM137665 and JW is supported by NIH R01-GM115622. The content is solely the responsibility of the authors and does not necessarily represent the official views of their sponsors.
The authors report no competing interests relevant to the work summarised in the current manuscript. JW is the founder of Chemical Biology Probes LLC and holds a patent related to the GSH probes used in this study. JW also serves as a consultant for CoRegen Inc.
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Yu, W., Chen, Y., Putluri, N. et al. Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state. Br J Cancer 128, 2013–2024 (2023). https://doi.org/10.1038/s41416-023-02253-7