51. PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma
- Author
-
Sarah D. Edge, Isaline Renard, Stephen J. Archibald, Andrew W Beavis, Chun Li, Emily Pyne, Hannah Moody, Christopher Cawthorne, Stephen G. Maher, Isabel M. Pires, and Rajarshi Roy
- Subjects
EXPRESSION ,Oncology ,medicine.medical_specialty ,Standard of care ,Esophageal Neoplasms ,medicine.medical_treatment ,Treatment outcome ,GDC-0941 ,MEDLINE ,Oesophageal adenocarcinoma ,Adenocarcinoma ,PATHWAY ,ACTIVATION ,Mice ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Neoadjuvant therapy ,030304 developmental biology ,Therapeutic strategy ,0303 health sciences ,Science & Technology ,Full Paper ,CHEMORESISTANCE ,Manchester Cancer Research Centre ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Radiology, Nuclear Medicine & Medical Imaging ,PATHOLOGICAL RESPONSE ,General Medicine ,CANCER ,Neoadjuvant Therapy ,Treatment Outcome ,030220 oncology & carcinogenesis ,CELLS ,METASTASIS ,Female ,business ,Life Sciences & Biomedicine ,PREOPERATIVE CHEMORADIOTHERAPY ,Neoadjuvant chemoradiotherapy - Abstract
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.
- Published
- 2021