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dc.contributor.authorPancholi, S
dc.contributor.authorLeal, MF
dc.contributor.authorRibas, R
dc.contributor.authorSimigdala, N
dc.contributor.authorSchuster, E
dc.contributor.authorChateau-Joubert, S
dc.contributor.authorZabaglo, L
dc.contributor.authorHills, M
dc.contributor.authorDodson, A
dc.contributor.authorGao, Q
dc.contributor.authorJohnston, SR
dc.contributor.authorDowsett, M
dc.contributor.authorCosulich, SC
dc.contributor.authorMaragoni, E
dc.contributor.authorMartin, L-A
dc.date.accessioned2019-12-06T13:53:54Z
dc.date.issued2019-12-04
dc.identifier.citationBreast cancer research : BCR, 2019, 21 (1), pp. 135 - ?
dc.identifier.issn1465-5411
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3435
dc.identifier.eissn1465-542X
dc.identifier.doi10.1186/s13058-019-1222-0
dc.description.abstractBACKGROUND: Endocrine therapies are still the main strategy for the treatment of oestrogen receptor-positive (ER+) breast cancers (BC), but resistance remains problematic. Cross-talk between ER and PI3K/AKT/mTORC has been associated with ligand-independent transcription of ER. We have previously reported the anti-proliferative effects of the combination of everolimus (an mTORC1 inhibitor) with endocrine therapy in resistance models, but potential routes of escape via AKT signalling can lead to resistance; therefore, the use of dual mTORC1/2 inhibitors has met with significant interest. METHODS: To address this, we tested the effect of vistusertib, a dual mTORC1 and mTORC2 inhibitor, in a panel of endocrine-resistant and endocrine-sensitive ER+ BC cell lines, with varying PTEN, PIK3CA and ESR1 mutation status. End-points included proliferation, cell signalling, cell cycle and effect on ER-mediated transcription. Two patient-derived xenografts (PDX) modelling endocrine resistance were used to assess the efficacy of vistusertib, fulvestrant or the combination on tumour progression, and biomarker studies were conducted using immunohistochemistry and RNA-seq technologies. RESULTS: Vistusertib caused a dose-dependent decrease in proliferation of all the cell lines tested and reduced abundance of mTORC1, mTORC2 and cell cycle markers, but caused an increase in abundance of EGFR, IGF1R and ERBB3 in a context-dependent manner. ER-mediated transcription showed minimal effect of vistusertib. Combined therapy of vistusertib with fulvestrant showed synergy in two ER+ PDX models of resistance to endocrine therapy and delayed tumour progression after cessation of therapy. CONCLUSIONS: These data support the notion that models of acquired endocrine resistance may have a different sensitivity to mTOR inhibitor/endocrine therapy combinations.
dc.formatElectronic
dc.format.extent135 - ?
dc.languageeng
dc.language.isoeng
dc.publisherBMC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleCombination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer.
dc.typeJournal Article
dcterms.dateAccepted2019-10-30
rioxxterms.versionofrecord10.1186/s13058-019-1222-0
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-12-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBreast cancer research : BCR
pubs.issue1
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrine Therapy Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
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/Endocrine Therapy Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
pubs.publication-statusPublished
pubs.volume21
pubs.embargo.termsNot known
icr.researchteamEndocrine Therapy Resistance
icr.researchteamEndocrinology
dc.contributor.icrauthorPancholi, Sunil
dc.contributor.icrauthorSchuster, Eugene
dc.contributor.icrauthorGao, Qiong


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