Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress.

Wangjie Yu,Jeffrey N Myers,Trung Nguyen,Stephen Y Lai,Dodge Baluya,Nagireddy Putluri,Michael A Mancini,Cristian Coarfa,Julien Dubrulle,Jonathan C Pang,Vasanta Putluri,Yunyun Chen,Vlad C Sandulache,Matthew J Robertson,Fabio Stossi

doi:10.3390/cancers12061670

Abstract

Background: Cisplatin (CDDP) is commonly utilized in the treatment of advanced solid tumors including head and neck squamous cell carcinoma (HNSCC). Cisplatin response remains highly variable among individual tumors and development of cisplatin resistance is common. We hypothesized that development of cisplatin resistance is partially driven by metabolic reprogramming. Methods: Using a pre-clinical HNSCC model and an integrated approach to steady state metabolomics, metabolic flux and gene expression data we characterized the interaction between cisplatin resistance and metabolic reprogramming. Results: Cisplatin toxicity in HNSCC was driven by generation of intra-cellular oxidative stress. This was validated by demonstrating that acquisition of cisplatin resistance generates cross-resistance to ferroptosis agonists despite the fact that cisplatin itself does not trigger ferroptosis. Acquisition of cisplatin resistance dysregulated the expression of genes involved in amino acid, fatty acid metabolism and central carbon catabolic pathways, enhanced glucose catabolism and serine synthesis. Acute cisplatin exposure increased intra-tumoral levels of S-methyl-5-thiadenosine (MTA) precursors and metabotoxins indicative of generalized oxidative stress. Conclusions: Acquisition of cisplatin resistance is linked to metabolic recovery from oxidative stress. Although this portends poor effectiveness for directed metabolic targeting, it supports the potential for biomarker development of cisplatin effectiveness using an integrated approach.

Highlights

Cisplatin (CDDP) is commonly utilized in the treatment of advanced solid tumors including head and neck squamous cell carcinoma (HNSCC)
Cisplatin exposure generates a metabolic signature which expands through common nodes into non central carbon processing pathways designed to support the stress condition
Diffuse distribution of metabolic stress across multiple overlapping pathways suggests that a single metabolic inhibitor is unlikely to generate profound cisplatin sensitization in this tumor type

Summary

Introduction

Cisplatin (CDDP) is commonly utilized in the treatment of advanced solid tumors including head and neck squamous cell carcinoma (HNSCC). We have shown that generation of oxidative stress either through application of ionizing radiation (IR) or platinum derivatives triggers acute, reversible metabolic changes in a variety of tumor models including HNSCC [7,8,9,10]. This has allowed us to develop a relatively quantitative, albeit indirect relationship between metabolic perturbations linked to carbon flux and generation of intra-cellular oxidative stress and DNA damage [7,8,9,10]. Identifying metabolic pathways key to cisplatin processing could allow us to develop potentially sensitive and specific biomarker signatures for relative cisplatin responsiveness, a clinical deliverable which has heretofore escaped characterization

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Discussion

Conclusion