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

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 miR-187 overexpression enhanced radiosensitivity and upregulated . 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. 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 and as a single agent . Radiation response was assessed via clonogenic assay.

RESULTS

PTEN expression was significantly decreased in neo-CRT non-responders. MiR-187 overexpression significantly upregulated expression and inhibited downstream PI3K signalling . GDC-0941 significantly reduced viability and enhanced radiation response and led to tumour growth inhibition as a single agent .

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.