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dc.contributor.authorIp, LRH
dc.contributor.authorPoulogiannis, G
dc.contributor.authorViciano, FC
dc.contributor.authorSasaki, J
dc.contributor.authorKofuji, S
dc.contributor.authorSpanswick, VJ
dc.contributor.authorHochhauser, D
dc.contributor.authorHartley, JA
dc.contributor.authorSasaki, T
dc.contributor.authorGewinner, CA
dc.date.accessioned2020-07-28T13:30:01Z
dc.date.issued2015-04
dc.identifier.citationOncotarget, 2015, 6 (12), pp. 10548 - 10562
dc.identifier.issn1949-2553
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3879
dc.identifier.eissn1949-2553
dc.identifier.doi10.18632/oncotarget.3307
dc.description.abstractTreatment options for ovarian cancer patients remain limited and overall survival is less than 50% despite recent clinical advances. The lipid phosphatase inositol polyphosphate 4-phosphatase type II (INPP4B) has been described as a tumor suppressor in the PI3K/Akt pathway with loss of expression found most pronounced in breast, ovarian cancer and melanoma. Using microarray technology we identified a DNA repair defect in INPP4B-deficient cells, which we further characterized by comet assays and quantification of γH2AX, RAD51 and 53BP1 foci formation. INPP4B loss resulted in significantly increased sensitivity towards PARP inhibition, comparable to loss of BRCA1 in two- and three-dimensional in vitro models, as well as in in vivo xenograft models. Mechanistically, we discovered that INPP4B forms a protein complex with the key players of DNA repair, ATR and BRCA1, in GST pulldown and 293T overexpression assays, and INPP4B loss affects BRCA1, ATM and ATR protein stability resulting in the observed DNA repair defect. Given that INPP4B loss has been found in 40% of ovarian cancer patients, this study provides the rationale for establishing INPP4B as a biomarker of PARP inhibitor response, and consequently offers novel therapeutic options for a significant subset of patients. Loss of the tumor suppressor inositol polyphosphate 4-phosphatase type II (INPP4B) results in a DNA repair defect due to concomitant loss of BRCA1, ATR and ATM and can be therapeutically targeted with PARP inhibitors.
dc.formatPrint
dc.format.extent10548 - 10562
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectAnimals
dc.subjectMice, Inbred NOD
dc.subjectHumans
dc.subjectMice
dc.subjectMice, SCID
dc.subjectBreast Neoplasms
dc.subjectOvarian Neoplasms
dc.subjectPhosphoric Monoester Hydrolases
dc.subjectBRCA1 Protein
dc.subjectXenograft Model Antitumor Assays
dc.subjectTransfection
dc.subjectDNA Repair
dc.subjectGenes, Tumor Suppressor
dc.subjectFemale
dc.subjectHEK293 Cells
dc.subjectTranscriptome
dc.subjectAtaxia Telangiectasia Mutated Proteins
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.titleLoss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment.
dc.typeJournal Article
dcterms.dateAccepted2015-02-08
rioxxterms.versionofrecord10.18632/oncotarget.3307
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2015-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfOncotarget
pubs.issue12
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Signalling & Cancer Metabolism
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Signalling & Cancer Metabolism
pubs.publication-statusPublished
pubs.volume6
pubs.embargo.termsNot known
icr.researchteamSignalling & Cancer Metabolismen_US
dc.contributor.icrauthorPoulogiannis, Georgiosen


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