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

Liu, David S., Duong, Cuong P., Haupt, Sue, Montgomery, Karen G., House, Colin M., Azar, Walid J., Pearson, Helen B. ORCID: https://orcid.org/0000-0002-3284-0843, Fisher, Oliver M., Read, Matthew, Guerra, Glen R., Haupt, Ygal, Cullinane, Carleen, Wiman, Klas G., Abrahmsen, Lars, Phillips, Wayne A. and Clemons, Nicholas J. 2017. Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nature Communications 8 , 14844. 10.1038/ncomms14844

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	Nature Publishing Group
ISSN:	2041-1723
Date of First Compliant Deposit:	18 August 2017
Date of Acceptance:	3 February 2017
Last Modified:	01 Jul 2023 18:28
URI:	https://orca.cardiff.ac.uk/id/eprint/103775

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