Show simple item record

dc.contributor.authorLiu, DS
dc.contributor.authorDuong, CP
dc.contributor.authorHaupt, S
dc.contributor.authorMontgomery, KG
dc.contributor.authorHouse, CM
dc.contributor.authorAzar, WJ
dc.contributor.authorPearson, HB
dc.contributor.authorFisher, OM
dc.contributor.authorRead, M
dc.contributor.authorGuerra, GR
dc.contributor.authorHaupt, Y
dc.contributor.authorCullinane, C
dc.contributor.authorWiman, KG
dc.contributor.authorAbrahmsen, L
dc.contributor.authorPhillips, WA
dc.contributor.authorClemons, NJ
dc.date.accessioned2021-02-04T00:07:03Z
dc.date.available2021-02-04T00:07:03Z
dc.date.issued2017-03-28
dc.identifierpii: ncomms14844
dc.identifier.citationLiu, D. S., Duong, C. P., Haupt, S., Montgomery, K. G., House, C. M., Azar, W. J., Pearson, H. B., Fisher, O. M., Read, M., Guerra, G. R., Haupt, Y., Cullinane, C., Wiman, K. G., Abrahmsen, L., Phillips, W. A. & Clemons, N. J. (2017). Inhibiting the system x((C)over-bar)/glutathione axis selectively targets cancers with mutant-p53 accumulation. NATURE COMMUNICATIONS, 8 (1), https://doi.org/10.1038/ncomms14844.
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/11343/259034
dc.description.abstractTP53, 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.
dc.languageEnglish
dc.publisherNATURE PUBLISHING GROUP
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleInhibiting the system x((C)over-bar)/glutathione axis selectively targets cancers with mutant-p53 accumulation
dc.typeJournal Article
dc.identifier.doi10.1038/ncomms14844
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.affiliation.departmentSurgery (St Vincent's)
melbourne.affiliation.department
melbourne.affiliation.departmentClinical Pathology
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.source.titleNature Communications
melbourne.source.volume8
melbourne.source.issue1
melbourne.identifier.nhmrc1120293
dc.rights.licenseCC BY
melbourne.elementsid1196773
melbourne.contributor.authorClemons, Nicholas
melbourne.contributor.authorDuong, Cuong
melbourne.contributor.authorGuerra, Glen Robert
melbourne.contributor.authorHaupt, Ygal
melbourne.contributor.authorPhillips, Wayne
melbourne.contributor.authorCullinane, Carleen
melbourne.contributor.authorHaupt, Susan
melbourne.contributor.authorLiu, David
melbourne.contributor.authorPEARSON, HELEN
melbourne.contributor.authorRead, Matthew
melbourne.contributor.authorRead, Matthew
dc.identifier.eissn2041-1723
melbourne.identifier.fundernameidNHMRC, 1120293
melbourne.accessrightsOpen Access


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record