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

Wangie Yu, Yunyun Chen, Nagireddy Putluri, Abdullah Osman, Cristian Coarfa, Vasanta Putluri, Abu H.M. Kamal, Jennifer Kay Asmussen, Panagiotis Katsonis, Jeffrey N. Myers, Stephen Y. Lai, Wuhao Lu, Clifford C. Stephan, Reid T. Powell, Faye M. Johnson, Heath D. Skinner, Jawad Kazi, Kazi Mokim Ahmed, Linghao Hu, Addison ThreetMatthew D. Meyer, James A. Bankson, Tony Wang, Jack Davis, Kirby R. Parker, Madison A. Harris, Mokryun L. Baek, Gloria V. Echeverria, Xiaoli Qi, Jin Wang, Andy I. Frederick, Alex J. Walsh, Olivier Lichtarge, Mitchell J. Frederick, Vlad C. Sandulache

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
JournalBritish Journal of Cancer
StateAccepted/In press - 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state'. Together they form a unique fingerprint.

Cite this