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Cellular and Molecular Biology

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state

British Journal of Cancer volume 128, pages 2013–2024 (2023)Cite this article

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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.

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Fig. 1: Mutational and transcriptional shifts associated with CDDP resistance.
Fig. 2: Activation of Nrf2 in CDDP-resistant clones.
Fig. 3: Protein validation of Nrf2 activation and metabolic reprogramming.
Fig. 4: CDDP-resistant cells have an enhanced reductive potential.
Fig. 5: CDDP-resistant cells have reduced energy production.
Fig. 6: Differential carbon flux in CDDP-resistant clones.

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Data availability

The data generated in this study are available within the article and its supplementary data files.

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Funding

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.

Author information

Authors and Affiliations

  1. Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA

    Wangie Yu, Wuhao Lu, Jawad Kazi, Kazi Mokim Ahmed, Tony Wang, Jack Davis, Kirby R. Parker, Madison A. Harris, Mitchell J. Frederick & Vlad C. Sandulache

  2. Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yunyun Chen, Abdullah Osman, Jeffrey N. Myers & Stephen Y. Lai

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Nagireddy Putluri, Cristian Coarfa, Mokryun L. Baek, Gloria V. Echeverria, Jin Wang & Vlad C. Sandulache

  4. Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA

    Cristian Coarfa

  5. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Cristian Coarfa, Mokryun L. Baek & Gloria V. Echeverria

  6. Advanced Technology core, Dan Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Vasanta Putluri & Abu H. M. Kamal

  7. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Jennifer Kay Asmussen, Panagiotis Katsonis & Olivier Lichtarge

  8. Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Stephen Y. Lai

  9. Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Stephen Y. Lai

  10. Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA

    Clifford C. Stephan & Reid T. Powell

  11. Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA

    Clifford C. Stephan & Reid T. Powell

  12. Department of Thoracic Head and Neck Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Faye M. Johnson

  13. Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Heath D. Skinner

  14. Biomedical Engineering, Texas A&M University, College Station, TX, USA

    Linghao Hu, Addison Threet & Alex J. Walsh

  15. Shared Equipment Authority, Rice University, Houston, TX, USA

    Matthew D. Meyer

  16. Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    James A. Bankson

  17. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    Mokryun L. Baek & Gloria V. Echeverria

  18. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Mokryun L. Baek & Gloria V. Echeverria

  19. Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, USA

    Xiaoli Qi, Jin Wang & Olivier Lichtarge

  20. School of Electrical and Computer Engineering Undergraduate Department, Cornell University, NY, USA

    Andy I. Frederick

  21. Department of Biochemistry & Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    Olivier Lichtarge

  22. Program in Quantitative and Computational Biosciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    Olivier Lichtarge

  23. Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    Olivier Lichtarge

  24. Computational and Integrative Biomedical Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    Olivier Lichtarge

  25. Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA

    Vlad C. Sandulache

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  1. Wangie Yu
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Contributions

Conceptualisation: WY, MJF, VCS and JNM; funding: VCS and JNM; reagent generation: WY, YC, JAB, SYL, AO and AJW; assay design and development: WY, YC, NP, VP, CC, MJF, AHMK, JKA, PK, OL, and MDM; data generation: WY, YC, NP, AO, CC, VP, AHMK, JKA, PK, WL, CCS, RTP, JK, KMA, LU, AT, MTD, JAN, TW, JD, KRP, MAH, MLB, GVE, XQ, JW, AIF, AJW, OL, VCS and MJF; data analysis: WY, YC, NP, AO, CC, VP, AHMK, JKA, PK, WL, CCS, RTP, JK, KMA, LU, AT, MTD, JAN, MLB, GVE, XQ, JW, AIF, AJW, OL, VCS and MJF; manuscript drafting: WY, YC, NP, CC, VCS, JNM and MJF; manuscript review: WY, YC, NP, AO, CC, VP, AHMK, JKA, PK, WL, CCS, RTP, JK, KMA, LU, AT, MTD, JAN, MLB, GVE, XQ, JW, AIF, AJW, OL, VCS, MJF, HDS and FMJ.

Corresponding authors

Correspondence to Mitchell J. Frederick or Vlad C. Sandulache.

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Competing interests

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

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