Inhibiting the system xC - /glutathione axis selectively targets cancers with mutant-p53 accumulation

David Shi Hao Liu, Cuong Phu Duong, Sue Haupt, Karen G Montgomery, Colin M House, Walid J Azar, Helen B. Pearson, Oliver M. Fisher, Matthew Read, Glen R. Guerra, Ygal Haupt, Carleen M Cullinane, Klas G. Wiman, Lars Abrahmsen, Wayne A. Phillips, Nicholas J Clemons

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Abstract

TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system xC -, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System xC - inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that SLC7A11 expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system xC - antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11-glutathione axis.

Original languageEnglish
Article number14844
Number of pages14
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 28 Mar 2017
Externally publishedYes

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