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dc.contributor.authorLynch, James T
dc.contributor.authorPolanska, UM
dc.contributor.authorHancox, U
dc.contributor.authorDelpuech, O
dc.contributor.authorMaynard, J
dc.contributor.authorTrigwell, Cath
dc.contributor.authorEberlein, Cath
dc.contributor.authorLenaghan, C
dc.contributor.authorPolanski, Radoslaw
dc.contributor.authorAvivar-Valderas, A
dc.contributor.authorCumberbatch, M
dc.contributor.authorKlinowska, T
dc.contributor.authorCritchlow, SE
dc.contributor.authorCruzalegui, F
dc.contributor.authorBarry, ST
dc.date.accessioned2018-12-10T11:48:49Z
dc.date.available2018-12-10T11:48:49Z
dc.date.issued2018en
dc.identifier.citationLynch JT, Polanska UM, Hancox U, Delpuech O, Maynard J, Trigwell C, et al. Combined inhibition of PI3K beta and mTOR Inhibits growth of PTEN-null tumors. Mol Cancer Ther. 2018 Nov;17(11):2309-19.en
dc.identifier.pmid30097489en
dc.identifier.doi10.1158/1535-7163.MCT-18-0183en
dc.identifier.urihttp://hdl.handle.net/10541/621377
dc.description.abstractLoss of the tumor suppressor PTEN confers a tumor cell dependency on the PI3K? isoform. Achieving maximal inhibition of tumor growth through PI3K pathway inhibition requires sustained inhibition of PI3K signaling; however, efficacy is often limited by suboptimal inhibition or reactivation of the pathway. To select combinations that deliver comprehensive suppression of PI3K signaling in PTEN-null tumors, the PI3K? inhibitor AZD8186 was combined with inhibitors of kinases implicated in pathway reactivation in an extended cell proliferation assay. Inhibiting PI3K? and mTOR gave the most effective antiproliferative effects across a panel of PTEN-null tumor cell lines. The combination of AZD8186 and the mTOR inhibitor vistusertib was also effective in vivo controlling growth of PTEN-null tumor models of TNBC, prostate, and renal cancers. In vitro, the combination resulted in increased suppression of pNDRG1, p4EBP1, as well as HMGCS1 with reduced pNDRG1 and p4EBP1 more closely associated with effective suppression of proliferation. In vivo biomarker analysis revealed that the monotherapy and combination treatment consistently reduced similar biomarkers, while combination increased nuclear translocation of the transcription factor FOXO3 and reduction in glucose uptake. These data suggest that combining the PI3K? inhibitor AZD8186 and vistusertib has potential to be an effective combination treatment for PTEN-null tumors. en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1158/1535-7163.MCT-18-0183en
dc.titleCombined inhibition of PI3K beta and mTOR Inhibits growth of PTEN-null tumors.en
dc.typeArticleen
dc.contributor.departmentBioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridgeen
dc.identifier.journalMolecular Cancer Therapeuticsen
refterms.dateFOA2020-04-21T13:03:43Z


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