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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., 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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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
Publisher: Nature Publishing Group
ISSN: 2041-1723
Date of First Compliant Deposit: 18 August 2017
Date of Acceptance: 3 February 2017
Last Modified: 03 Apr 2019 11:19

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