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    PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma

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    Publication date
    2021-01
    Author
    Edge, S.D.
    Renard, I.
    Pyne, E.
    Moody, Hannah L.
    Roy, R.
    Beavis, A.W.
    Archibald, S.J.
    Cawthorne, C.J.
    Maher, S.G.
    Pires, I.M.
    Keyword
    Oesophageal adenocarcinoma
    PI3K inhibition
    Neoadjuvant chemoradiotherapy
    Peer-Reviewed
    Yes
    Open Access status
    Not Open Access
    
    Metadata
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    Abstract
    Neoadjuvant chemoradiotherapy (neo-CRT) prior to surgery is the standard of care for oesophageal adenocarcinoma (OAC) patients. Unfortunately, most patients fail to respond to treatment. MiR-187 was previously shown to be downregulated in neo-CRT non-responders, whist in vitro miR-187 overexpression enhanced radiosensitivity and upregulated PTEN. This study evaluates the role of miR-187 and downstream PI3K signalling in radiation response in OAC. The effect of miR-187 overexpression on downstream PI3K signalling was evaluated in OAC cell lines by qPCR and Western blotting. PTEN expression was analysed in OAC pre-treatment biopsies of neo-CRT responders and non-responders. Pharmacological inhibition of PI3K using GDC-0941 was evaluated in combination with radiotherapy in two-dimensional and three-dimensional OAC models in vitro and as a single agent in vivo. Radiation response in vitro was assessed via clonogenic assay. PTEN expression was significantly decreased in neo-CRT non-responders. MiR-187 overexpression significantly upregulated PTEN expression and inhibited downstream PI3K signalling in vitro. GDC-0941 significantly reduced viability and enhanced radiation response in vitro and led to tumour growth inhibition as a single agent in vivo. Targeting of PI3K signalling is a promising therapeutic strategy for OAC patients who have repressed miR-187 expression and do not respond to conventional neo-CRT. This is the first study evaluating the effect of PI3K inhibition on radiosensitivity in OAC, with a particular focus on patients that do not respond to neo-CRT. We have shown for the first time that targeting of PI3K signalling is a promising alternative therapeutic strategy for OAC patients who do not respond to conventional neo-CRT.
    URI
    http://hdl.handle.net/10454/18357
    Version
    No full-text in the repository
    Citation
    Edge SD, Renard I, Pyne E et al (2021) PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma. British Journal of Radiology. 94(1119)
    Link to publisher’s version
    https://doi.org/10.1259/bjr.20201191
    Type
    Article
    Collections
    Life Sciences Publications

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