TY - JOUR
T1 - Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state
AU - Yu, Wangie
AU - Chen, Yunyun
AU - Putluri, Nagireddy
AU - Osman, Abdullah
AU - Coarfa, Cristian
AU - Putluri, Vasanta
AU - Kamal, Abu H.M.
AU - Asmussen, Jennifer Kay
AU - Katsonis, Panagiotis
AU - Myers, Jeffrey N.
AU - Lai, Stephen Y.
AU - Lu, Wuhao
AU - Stephan, Clifford C.
AU - Powell, Reid T.
AU - Johnson, Faye M.
AU - Skinner, Heath D.
AU - Kazi, Jawad
AU - Ahmed, Kazi Mokim
AU - Hu, Linghao
AU - Threet, Addison
AU - Meyer, Matthew D.
AU - Bankson, James A.
AU - Wang, Tony
AU - Davis, Jack
AU - Parker, Kirby R.
AU - Harris, Madison A.
AU - Baek, Mokryun L.
AU - Echeverria, Gloria V.
AU - Qi, Xiaoli
AU - Wang, Jin
AU - Frederick, Andy I.
AU - Walsh, Alex J.
AU - Lichtarge, Olivier
AU - Frederick, Mitchell J.
AU - Sandulache, Vlad C.
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/6/15
Y1 - 2023/6/15
N2 - 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.
AB - 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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U2 - 10.1038/s41416-023-02253-7
DO - 10.1038/s41416-023-02253-7
M3 - Article
C2 - 37012319
AN - SCOPUS:85151534086
SN - 0007-0920
VL - 128
SP - 2013
EP - 2024
JO - British journal of cancer
JF - British journal of cancer
IS - 11
ER -