Abstract 3806: Investigating the role of miRNA-34a in the resistance of esophageal adenocarcinoma to neoadjuvant chemoradiation therapy
Authors: Cahill Christina , Maher Stephen G. , O'Brien Rebecca , Wang Wei-Lin Winnie , Reynolds John V. , O'Sullivan Jacintha , Lynam-Lennon Niamh 
Published: June 2023

Background: The current standard of care for locally advanced esophageal adenocarcinoma (EAC) involves neo-adjuvant chemoradiation therapy (neo-CRT) followed by surgery. However, response to neo-CRT is poor and resistance remains a significant barrier to effective treatment. There are currently no clinical biomarkers to predict treatment response in EAC. Evidence supports a role for microRNA-34a (miR-34a) as a tumor suppressor in cancer, however, the role of miR-34a in the tumor response to therapy in EAC is largely unknown.

Methods: Irradiation of EAC cell lines was performed using an Xstrahl RS225 X-ray irradiator at a clinically-relevant dose of 2 Gy. Radiosensitivity of EAC cell lines (OE33 P, OE33 R, OE33, OE19, Flo-1Par and Flo-1LM) was assessed by the gold standard clonogenic assay. miR-34a expression was assessed by qPCR. EAC tumor biopsies were obtained from consenting patients undergoing diagnostic endoscopy. Pathological response of the resected tumor was assigned by a pathologist using the Mandard Tumor Regression scale. miRTarBase and KEGG pathway analysis were used to identify predicted target genes and pathways of miR-34a.

Results: miR-34a was demonstrated to be expressed in a panel of EAC cell lines (OE33 P, OE33 R, OE19, Flo-1Par and Flo-1LM cells). Interestingly, miR-34a expression was significantly decreased in EAC cell line models of both acquired radioresistance (OE33 R) and inherent radioresistance (OE19). miR-34a was also significantly decreased in a model of radioresistant metastatic EAC (Flo-1LM). Supporting in vitro data, in pre-treatment tumor biopsies from EAC patients (n=18), miR-34a was significantly decreased in patients having a subsequent poor pathological response to neo-CRT, when compared to patients having a good pathological response to neo-CRT. Target and pathway analysis demonstrated miR-34a-mediated regulation of genes and pathways associated with treatment resistance, including the complement system, cellular metabolism and p53 signaling, among others.

Conclusion: Decreased miR-34a expression is associated with radioresistance across a panel of in vitro EAC models and in pre-treatment tumor biopsies from EAC patients having a poor pathological response to neo-CRT. This highlights a potential role for miR-34a as a novel biomarker predicting response to neo-CRT in EAC. Analysis of validated and predicted gene targets of miR-34a identified a number of pathways associated with treatment resistance. We are currently investigating the functional role of miR-34a in modulating tumor response to radiation in vitro to determine its potential as a novel therapeutic target to boost treatment response in EAC.

Citation Format: Christina Cahill, Stephen G. Maher, Rebecca O'Brien, Wei-Lin Winnie Wang, John V. Reynolds, Jacintha O'Sullivan, Niamh Lynam-Lennon. Investigating the role of miRNA-34a in the resistance of esophageal adenocarcinoma to neoadjuvant chemoradiation therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3806.