RT Journal Article
SR Electronic
T1 PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.23.351981
DO 10.1101/2020.10.23.351981
A1 Edge, Sarah D.
A1 Renard, Isaline
A1 Pyne, Emily
A1 Moody, Hannah
A1 Roy, Rajarshi
A1 Beavis, Andrew W.
A1 Archibald, Stephen J.
A1 Cawthorne, Christopher J.
A1 Maher, Stephen G.
A1 Pires, Isabel M.
YR 2020
UL http://biorxiv.org/content/early/2020/10/23/2020.10.23.351981.abstract
AB Objectives Neoadjuvant chemo-radiotherapy (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 radio-sensitivity 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 2D and 3D 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.Conclusions 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 radio-sensitivity in OAC, with a particular focus on patients that do not respond to neo-CRT. We have shown for the 1st time that targeting of PI3K signalling is a promising alternative therapeutic strategy for OAC patients who do not respond to conventional neo-CRT.Competing Interest StatementThe authors have declared no competing interest.