TP53 mutations in head and neck cancer cells determine the Warburg phenotypic switch creating metabolic vulnerabilities and therapeutic opportunities for stratified therapies.

Mark D Wilkie,Carlos P Rubbi,Andrew S Lau,Mark T Boyd,Nikolina Vlatković,Emad A Anaam,Terence M Jones

doi:10.1016/j.canlet.2020.02.032

Abstract

Patients with mutated TP53 have been identified as having comparatively poor outcomes compared to those retaining wild-type p53 in many cancers, including squamous cell carcinomas of the head and neck (SCCHN). We have examined the role of p53 in regulation of metabolism in SCCHN cells and find that loss of p53 function determines the Warburg effect in these cells. Moreover, this metabolic adaptation to loss of p53 function creates an Achilles’ heel for tumour cells that can be exploited for potential therapeutic benefit. Specifically, cells lacking normal wild-type p53 function, whether through mutation or RNAi-mediated downregulation, display a lack of metabolic flexibility, becoming more dependent on glycolysis and losing the ability to increase energy production from oxidative phosphorylation. Thus, cells that have compromised p53 function can be sensitised to ionizing radiation by pre-treatment with a glycolytic inhibitor. These results demonstrate the deterministic role of p53 in regulating energy metabolism and provide proof of principle evidence for an opportunity for patient stratification based on p53 status that can be exploited therapeutically using current standard of care treatment with ionising radiation.

Highlights

One of the greatest challenges preventing the successful treatment of cancer derives from difficulties in developing treatment strategies that can distinguish tumour cells from normal and provide a substantial therapeutic index
These studies have raised several critical questions, not least of which are: i) To what extent does TP53 status determine metabolic changes in SCCHN cells, for example would reintroduction of wild-type p53 re-establish metabolic flexibility and ii) in a more quantitative sense, what is the impact of TP53 status on the absolute, rather than relative, levels of respiratory and glycolytic metabolism? The present study provides answers to both of these questions
Our data demonstrate that re-introduction of wild-type p53 can reverse the metabolic adaptation of p53 null mutant cells

Summary

Introduction

One of the greatest challenges preventing the successful treatment of cancer derives from difficulties in developing treatment strategies that can distinguish tumour cells from normal and provide a substantial therapeutic index. Whilst many therapeutic approaches have been developed that try to take advantage of oncogenic events such as translocations and activation of signalling pathways promoting cell proliferation and survival, loss of tumour suppressor function has proven largely refractory to attempts to target therapeutic interventions [5]. This is not really surprising, since it is conceptually challenging to envisage means to re-activate mutant gene function/s, but the loss of tumour suppressor gene function in mutant cells frequently creates other functional phenotypic consequences, and these are potentially amenable to targeted intervention. The p53 protein co-ordinates a wide range of cellular processes, primarily through its function

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Results

Conclusion