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    Combined inhibition of PI3K beta and mTOR Inhibits growth of PTEN-null tumors.

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    Authors
    Lynch, James T
    Polanska, UM
    Hancox, U
    Delpuech, O
    Maynard, J
    Trigwell, Cath
    Eberlein, Cath
    Lenaghan, C
    Polanski, Radoslaw
    Avivar-Valderas, A
    Cumberbatch, M
    Klinowska, T
    Critchlow, SE
    Cruzalegui, F
    Barry, ST
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    Affiliation
    Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge
    Issue Date
    2018
    
    Metadata
    Show full item record
    Abstract
    Loss 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. 
    Citation
    Lynch 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.
    Journal
    Molecular Cancer Therapeutics
    URI
    http://hdl.handle.net/10541/621377
    DOI
    10.1158/1535-7163.MCT-18-0183
    PubMed ID
    30097489
    Additional Links
    https://dx.doi.org/10.1158/1535-7163.MCT-18-0183
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1158/1535-7163.MCT-18-0183
    Scopus Count
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    All Paterson Institute for Cancer Research

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