PT  - JOURNAL ARTICLE
AU  - Edge, Sarah D.
AU  - Renard, Isaline
AU  - Pyne, Emily
AU  - Moody, Hannah
AU  - Roy, Rajarshi
AU  - Beavis, Andrew W.
AU  - Archibald, Stephen J.
AU  - Cawthorne, Christopher J.
AU  - Maher, Stephen G.
AU  - Pires, Isabel M.
TI  - PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma
AID  - 10.1101/2020.10.23.351981
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.23.351981
4099  - http://biorxiv.org/content/early/2020/10/23/2020.10.23.351981.short
4100  - http://biorxiv.org/content/early/2020/10/23/2020.10.23.351981.full
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.