title: Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation.
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.
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Liu
authors.affiliation: Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
authors.forename: Cuong P
authors.initials: CP
authors.lastname: Duong
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
authors.forename: Sue
authors.initials: S
authors.lastname: Haupt
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
authors.forename: Karen G
authors.initials: KG
authors.lastname: Montgomery
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
authors.forename: Colin M
authors.initials: CM
authors.lastname: House
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
authors.forename: Walid J
authors.initials: WJ
authors.lastname: Azar
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Helen B
authors.initials: HB
authors.lastname: Pearson
authors.affiliation: Gastroesophageal Cancer Program, St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Fisher
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Read
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Glen R
authors.identifier: 0000-0002-2505-1643
authors.initials: GR
authors.lastname: Guerra
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Ygal
authors.initials: Y
authors.lastname: Haupt
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm SE-171 76, Sweden.
authors.forename: Klas G
authors.initials: KG
authors.lastname: Wiman
authors.affiliation: Aprea Therapeutics, Nobels väg 3, Solna 171 65, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Abrahmsen
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.|Department of Surgery (St Vincent's Hospital), The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Wayne A
authors.identifier: 0000-0002-7961-638X
authors.initials: WA
authors.lastname: Phillips
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Clemons
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011812:Quinuclidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D027182:Amino Acid Transport System y+; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011812:Quinuclidines; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; D016159:Tumor Suppressor Protein p53; D005978:Glutathione; C533410:eprenetapopt