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Nat Commun. 2017 Mar 28;8:14844. doi: 10.1038/ncomms14844.

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

Author information

1
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
2
Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
3
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
4
Gastroesophageal Cancer Program, St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales 2010, Australia.
5
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm SE-171 76, Sweden.
6
Aprea Therapeutics, Nobels väg 3, Solna 171 65, Sweden.
7
Department of Surgery (St Vincent's Hospital), The University of Melbourne, Parkville, Victoria 3010, Australia.

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.

PMID:
28348409
PMCID:
PMC5379068
DOI:
10.1038/ncomms14844
[Indexed for MEDLINE]
Free PMC Article

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