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dc.contributor.authorZecchin, D
dc.contributor.authorMoore, C
dc.contributor.authorMichailidis, F
dc.contributor.authorHorswell, S
dc.contributor.authorRana, S
dc.contributor.authorHowell, M
dc.contributor.authorDownward, J
dc.date.accessioned2020-08-26T15:46:05Z
dc.date.issued2020-08
dc.identifier.citationEMBO molecular medicine, 2020, 12 (8), pp. e11987 - ?
dc.identifier.issn1757-4676
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4024
dc.identifier.eissn1757-4684
dc.identifier.doi10.15252/emmm.202011987
dc.description.abstractTriple-negative breast cancer (TNBC) has poorer prognosis compared to other types of breast cancers due to the lack of effective therapies and markers for patient stratification. Loss of PTEN tumor suppressor gene expression is a frequent event in TNBC, resulting in over-activation of the PI 3-kinase (PI3K) pathway and sensitivity to its inhibition. However, PI3K pathway inhibitors show limited efficacy as monotherapies on these tumors. We report a whole-genome screen to identify targets whose inhibition enhanced the effects of different PI3K pathway inhibitors on PTEN-null TNBC. This identified a signaling network that relies on both the G protein-coupled receptor for thrombin (PAR1/F2R) and downstream G protein βγ subunits and also epidermal growth factor receptor (EGFR) for the activation of the PI3K isoform p110β and AKT. Compensation mechanisms involving these two branches of the pathway could bypass PI3K blockade, but combination targeting of both EGFR and PI3Kβ suppressed ribosomal protein S6 phosphorylation and exerted anti-tumor activity both in vitro and in vivo, suggesting a new potential therapeutic strategy for PTEN-null TNBC.
dc.formatPrint-Electronic
dc.format.extente11987 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleCombined targeting of G protein-coupled receptor and EGF receptor signaling overcomes resistance to PI3K pathway inhibitors in PTEN-null triple negative breast cancer.
dc.typeJournal Article
dcterms.dateAccepted2020-06-16
rioxxterms.versionofrecord10.15252/emmm.202011987
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfEMBO molecular medicine
pubs.issue8
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/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
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/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
pubs.publication-statusPublished
pubs.volume12
pubs.embargo.termsNot known
icr.researchteamLung Cancer Groupen_US
dc.contributor.icrauthorDownward, Julian David Harry


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