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    Inhibition of PI3K/BMX cell survival pathway sensitizes to BH3 mimetics in SCLC.

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    Authors
    Potter, Danielle S
    Galvin, Melanie
    Brown, Stewart
    Lallo, Alice
    Hodgkinson, Cassandra L
    Blackhall, Fiona H
    Morrow, Christopher J
    Dive, Caroline
    Affiliation
    Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester
    Issue Date
    2016-06
    
    Metadata
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    Abstract
    Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo These data add to a body of evidence that this combination should move toward the clinic. Mol Cancer Ther; 15(6); 1248-60. ©2016 AACR.
    Citation
    Inhibition of PI3K/BMX cell survival pathway sensitizes to BH3 mimetics in SCLC. 2016, 15 (6):1248-60 Mol Cancer Ther
    Journal
    Molecular Cancer Therapeutics
    URI
    http://hdl.handle.net/10541/614579
    DOI
    10.1158/1535-7163.MCT-15-0885
    PubMed ID
    27197306
    Type
    Article
    Language
    en
    ISSN
    1538-8514
    ae974a485f413a2113503eed53cd6c53
    10.1158/1535-7163.MCT-15-0885
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