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

DS Liu; CP Duong; S Haupt; KG Montgomery; CM House; WJ Azar; HB Pearson; OM Fisher; M Read; GR Guerra; Y Haupt; C Cullinane; KG Wiman; L Abrahmsen; WA Phillips; NJ Clemons

Journal article

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

DS Liu, CP Duong, S Haupt, KG Montgomery, CM House, WJ Azar, HB Pearson, OM Fisher, M Read, GR Guerra, Y Haupt, C Cullinane, KG Wiman, L Abrahmsen, WA Phillips, NJ Clemons

Nature Communications | NATURE PUBLISHING GROUP | Published : 2017

DOI: 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 t..

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University of Melbourne Researchers

Cuong Duong Author

Wayne Phillips Author

Nicholas Clemons Author

Glen Guerra Author

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Grants

Awarded by Victorian Cancer Agency

Funding Acknowledgements

This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Centres for Research Excellence Grant #1040947 (W.A.P.), a Translational Research Project Grant (TRP15012) from the Victorian Government Department of Health and Human Services through the Victorian Cancer Agency (W.A.P., N.J.C., C.P.D.), and a Peter MacCallum Cancer Foundation New Investigator grant (D.S.L.); D.S.L. was supported by Royal Australasian College of Surgeons (RACS) Foundation for Surgery John Loewenthal, Reg Worcester and Eric Bishop Fellowships, Cancer Therapeutics Scholarship (Cancer Therapeutics CRC) and NHMRC Postgraduate Research Scholarship; O.M.F. by a NHMRC Postgraduate Research Scholarship and a Swiss National Science Foundation Doc.Mobility Grant; M.R. by a RACS Thornell-Shore Memorial Scholarship and Melbourne University Sir Thomas Naghten Fitzgerald Scholarship; and G.R.G. by a RACS Foundation for Surgery Research Scholarship and a Covidien Colorectal Research Fellowship. N.J.C. is supported by a Victorian Cancer Agency Fellowship (MCRF16002) and an NHMRC Project Grant #1120293 (W.A.P., N.J.C., Y.H.). H.B.P. is supported by a Marie-Sklodowska Curie Actions/Ser Cymru COFUND fellowship. We thank Prof Johannes Zuber for providing the tet-inducible shRNA vector and Prof Ricky Johnstone, Prof Mark Dawson, Dr Daniella Brasacchio, Dr Liz Christie, and the Peter MacCallum Cancer Centre FACS, microscopy, functional genomics and animal core facilities, for their advice and/or technical assistance.