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dc.contributor.authorGris-Oliver, Aen_US
dc.contributor.authorPalafox, Men_US
dc.contributor.authorMonserrat, Len_US
dc.contributor.authorBrasó-Maristany, Fen_US
dc.contributor.authorÒdena, Aen_US
dc.contributor.authorSánchez-Guixé, Men_US
dc.contributor.authorIbrahim, YHen_US
dc.contributor.authorVillacampa, Gen_US
dc.contributor.authorGrueso, Jen_US
dc.contributor.authorParés, Men_US
dc.contributor.authorGuzmán, Men_US
dc.contributor.authorRodríguez, Oen_US
dc.contributor.authorBruna, Aen_US
dc.contributor.authorHirst, CSen_US
dc.contributor.authorBarnicle, Aen_US
dc.contributor.authorde Bruin, ECen_US
dc.contributor.authorReddy, Aen_US
dc.contributor.authorSchiavon, Gen_US
dc.contributor.authorArribas, Jen_US
dc.contributor.authorMills, GBen_US
dc.contributor.authorCaldas, Cen_US
dc.contributor.authorDienstmann, Ren_US
dc.contributor.authorPrat, Aen_US
dc.contributor.authorNuciforo, Pen_US
dc.contributor.authorRazavi, Pen_US
dc.contributor.authorScaltriti, Men_US
dc.contributor.authorTurner, NCen_US
dc.contributor.authorSaura, Cen_US
dc.contributor.authorDavies, BRen_US
dc.contributor.authorOliveira, Men_US
dc.contributor.authorSerra, Ven_US
dc.date.accessioned2020-05-22T13:58:45Z
dc.date.accessioned2020-05-22T14:03:05Z
dc.date.issued2020-07en_US
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (14), pp. 3720 - 3731en_US
dc.identifier.issn1078-0432en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3626
dc.identifier.doi10.1158/1078-0432.ccr-19-3324en_US
dc.description.abstractPURPOSE:AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel. EXPERIMENTAL DESIGN:Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel. RESULTS:Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K. CONCLUSIONS:This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.en_US
dc.formatPrint-Electronicen_US
dc.format.extent3720 - 3731en_US
dc.languageengen_US
dc.language.isoengen_US
dc.relation.replaceshttps://repository.icr.ac.uk/handle/internal/3625
dc.relation.replacesinternal/3625
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.titleGenetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-03-24en_US
rioxxterms.versionofrecord10.1158/1078-0432.ccr-19-3324en_US
rioxxterms.licenseref.startdate2020-07en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Researchen_US
pubs.issue14en_US
pubs.notesNot knownen_US
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Preclinical Modelling of Paediatric Cancer Evolution
pubs.publication-statusPublisheden_US
pubs.volume26en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMolecular Oncologyen_US
icr.researchteamPreclinical Modelling of Paediatric Cancer Evolutionen_US
dc.contributor.icrauthorTurner, Nicholasen_US
dc.contributor.icrauthorBruna Cabot, Alejandraen_US


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