Sarah D Edge
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.
Andrew W Beavis
Stephen J Archibald
Christopher J Cawthorne
Stephen J Maher
Dr Isabel Monteiro dos Santos Pires I.Pires@hull.ac.uk
Lecturer in Biomedical Science/ Head of the Hypoxia and Tumour Microenvironment group
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.
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|
|Publisher||British Institute of Radiology|
|Peer Reviewed||Peer Reviewed|
|Keywords||Oesophageal cancer; PI3K; miR-187; Radiation; PTEN|
This file is under embargo until Jan 13, 2022 due to copyright reasons.
Contact I.Pires@hull.ac.uk to request a copy for personal use.