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

Sarah D. Edge, Isaline Renard, Emily Pyne, View ORCID ProfileHannah Moody, View ORCID ProfileRajarshi Roy, View ORCID ProfileAndrew W. Beavis, View ORCID ProfileStephen J. Archibald, View ORCID ProfileChristopher J. Cawthorne, View ORCID ProfileStephen G. Maher, View ORCID ProfileIsabel M. Pires
doi: https://doi.org/10.1101/2020.10.23.351981
Sarah D. Edge
1Hypoxia and Tumour Microenvironment Lab, Department of Biomedical Sciences, Faculty of Health Sciences, University of Hull, UK
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Isaline Renard
2Positron Emission Tomography Centre, Department of Biomedical Sciences, Faculty of Health Sciences, University of Hull, UK
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Emily Pyne
1Hypoxia and Tumour Microenvironment Lab, Department of Biomedical Sciences, Faculty of Health Sciences, University of Hull, UK
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Hannah Moody
1Hypoxia and Tumour Microenvironment Lab, Department of Biomedical Sciences, Faculty of Health Sciences, University of Hull, UK
3Institute of Cancer Therapeutics; School of Medicine and Medical Sciences, University of Bradford, UK
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Rajarshi Roy
4Queen’s Centre for Oncology and Haematology, Castle Hill Hospital, Castle Rd, Cottingham HU16 5JQ, UK
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Andrew W. Beavis
5Department of Medical Physics, Queen’s Centre for Oncology, Hull University Teaching Hospitals NHS Trust, Cottingham, HU16 5JQ, UK
6Faculty of Health Sciences, University of Hull, Cottingham road, Hull, HU16 7RX, UK
7Faculty of Health and Well Being, Sheffield-Hallam University, Collegiate Crescent, Sheffield, S10 2BP
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Stephen J. Archibald
2Positron Emission Tomography Centre, Department of Biomedical Sciences, Faculty of Health Sciences, University of Hull, UK
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Christopher J. Cawthorne
2Positron Emission Tomography Centre, Department of Biomedical Sciences, Faculty of Health Sciences, University of Hull, UK
9Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium
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  • For correspondence: i.pires@hull.ac.uk maherst@tcd.ie christopher.cawthorne@kuleuven.be
Stephen G. Maher
10Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St. James’s Hospital, Dublin, Ireland
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  • For correspondence: i.pires@hull.ac.uk maherst@tcd.ie christopher.cawthorne@kuleuven.be
Isabel M. Pires
1Hypoxia and Tumour Microenvironment Lab, Department of Biomedical Sciences, Faculty of Health Sciences, University of Hull, UK
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  • For correspondence: i.pires@hull.ac.uk maherst@tcd.ie christopher.cawthorne@kuleuven.be
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Abstract

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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 23, 2020.
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PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma
Sarah D. Edge, Isaline Renard, Emily Pyne, Hannah Moody, Rajarshi Roy, Andrew W. Beavis, Stephen J. Archibald, Christopher J. Cawthorne, Stephen G. Maher, Isabel M. Pires
bioRxiv 2020.10.23.351981; doi: https://doi.org/10.1101/2020.10.23.351981
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PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma
Sarah D. Edge, Isaline Renard, Emily Pyne, Hannah Moody, Rajarshi Roy, Andrew W. Beavis, Stephen J. Archibald, Christopher J. Cawthorne, Stephen G. Maher, Isabel M. Pires
bioRxiv 2020.10.23.351981; doi: https://doi.org/10.1101/2020.10.23.351981

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