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

Edge, Sarah D; Renard, Isaline; Pyne, Emily; Li, Chun; Moody, Hannah; Roy, Rajarshi; Beavis, Andrew W; Archibald, Stephen J; Cawthorne, Christopher J; Maher, Stephen J; Pires, Isabel M.

Authors

Sarah D Edge

Isaline Renard

Emily Pyne

Chun Li

Hannah Moody

Rajarshi Roy

Andrew W Beavis

Stephen J Archibald

Christopher J Cawthorne

Stephen J Maher



Abstract

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. ADVANCES IN KNOWLEDGE: 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.

Citation

Edge, S. D., Beavis, A. W., Archibald, S. J., Cawthorne, C. J., Maher, S. G., Edge, S. D., …Pires, I. M. (2021). PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma. British Journal of Radiology, 94(1119), https://doi.org/10.1259/bjr.20201191

Journal Article Type Article
Acceptance Date Dec 23, 2020
Online Publication Date Jan 12, 2021
Publication Date Mar 1, 2021
Deposit Date Dec 23, 2020
Publicly Available Date Jan 13, 2022
Journal The British journal of radiology
Print ISSN 0007-1285
Electronic ISSN 1748-880X
Publisher British Institute of Radiology
Peer Reviewed Peer Reviewed
Volume 94
Issue 1119
Article Number 20201191
DOI https://doi.org/10.1259/bjr.20201191
Keywords Oesophageal cancer; PI3K; miR-187; Radiation; PTEN
Public URL https://hull-repository.worktribe.com/output/3681784
Publisher URL https://www.birpublications.org/doi/abs/10.1259/bjr.20201191