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

Edge, S. D.; Renard, I.; Pyne, E.; Moody, H.; Roy, R.; Beavis, A. W.; Archibald, S. J.; Cawthorne, C. J.; Maher, S. G.; Pires, I. M.

doi:10.1101/2020.10.23.351981

bioRxiv · 10.1101/2020.10.23.351981

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

Edge, S. D.·Renard, I.·Pyne, E.·Moody, H.·Roy, R.·Beavis, A. W.·Archibald, S. J.·Cawthorne, C. J.·Maher, S. G.·Pires, I. M.

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Abstract

ObjectivesNeoadjuvant 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. MethodsThe 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. ResultsPTEN 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. ConclusionsTargeting 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 knowledgeThis 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.

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Edge, S. D., Renard, I., Pyne, E., Moody, H., Roy, R., Beavis, A. W., Archibald, S. J., Cawthorne, C. J., Maher, S. G., Pires, I. M.. 2020-10-23. PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma. https://doi.org/10.1101/2020.10.23.351981

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