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    Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055).

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    Authors
    Holt, Sarah V
    Logie, A
    Davies, B
    Alferez, D
    Runswick, S
    Fenton, S
    Chresta, C
    Gu, Y
    Zhang, J
    Wu, Y
    Wilkinson, R
    Guichard, S
    Smith, P
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    Affiliation
    Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
    Issue Date
    2012-04-01
    
    Metadata
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    Abstract
    The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy.
    Citation
    Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055). 2012, 72 (7):1804-13 Cancer Res
    Journal
    Cancer Research
    URI
    http://hdl.handle.net/10541/251869
    DOI
    10.1158/0008-5472.CAN-11-1780
    PubMed ID
    22271687
    Type
    Article
    Language
    en
    ISSN
    1538-7445
    ae974a485f413a2113503eed53cd6c53
    10.1158/0008-5472.CAN-11-1780
    Scopus Count
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    All Paterson Institute for Cancer Research

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