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dc.contributor.authorMilton, CKen_US
dc.contributor.authorSelf, AJen_US
dc.contributor.authorClarke, PAen_US
dc.contributor.authorBanerji, Uen_US
dc.contributor.authorPiccioni, Fen_US
dc.contributor.authorRoot, DEen_US
dc.contributor.authorWhittaker, SRen_US
dc.date.accessioned2020-05-18T14:10:37Z
dc.date.issued2020-07en_US
dc.identifier.citationMolecular cancer therapeutics, 2020, 19 (7), pp. 1423 - 1435en_US
dc.identifier.issn1535-7163en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3612
dc.identifier.eissn1538-8514en_US
dc.identifier.doi10.1158/1535-7163.mct-19-1131en_US
dc.description.abstractKRAS mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic cancer have shown limited responses. Understanding the molecular basis for this lack of efficacy may direct future treatment strategies with emerging PI3K inhibitors. We sought new therapeutic approaches that synergize with PI3K inhibitors through pooled CRISPR modifier genetic screening and a drug combination screen. ERBB family receptor tyrosine kinase signaling and mTOR signaling were key modifiers of sensitivity to alpelisib and pictilisib. Inhibition of the ERBB family or mTOR was synergistic with PI3K inhibition in spheroid, stromal cocultures. Near-complete loss of ribosomal S6 phosphorylation was associated with synergy. Genetic alterations in the ERBB-PI3K signaling axis were associated with decreased survival of patients with pancreatic cancer. Suppression of the PI3K/mTOR axis is potentiated by dual PI3K and ERBB family or mTOR inhibition. Surprisingly, despite the presence of oncogenic KRAS, thought to bestow independence from receptor tyrosine kinase signaling, inhibition of the ERBB family blocks downstream pathway activation and synergizes with PI3K inhibitors. Further exploration of these therapeutic combinations is warranted for the treatment of pancreatic cancer.en_US
dc.formatPrint-Electronicen_US
dc.format.extent1423 - 1435en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleA Genome-scale CRISPR Screen Identifies the ERBB and mTOR Signaling Networks as Key Determinants of Response to PI3K Inhibition in Pancreatic Cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-04-06en_US
rioxxterms.versionofrecord10.1158/1535-7163.mct-19-1131en_US
rioxxterms.licenseref.startdate2020-07en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfMolecular cancer therapeuticsen_US
pubs.issue7en_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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.publication-statusPublisheden_US
pubs.volume19en_US
pubs.embargo.termsNot knownen_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
dc.contributor.icrauthorClarke, Paulen_US
dc.contributor.icrauthorBanerji, Udaien_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/