Abstract 1745: Targeting therapeutic resistance of esophageal adenocarcinoma through modulating the epithelial-to-mesenchymal transition via NFκB-mediated signaling
Authors: Zhang Yun , Weh Katherine M. , Howard Connor L. , Riethoven Jean-Jack , Clarke Jennifer L. , Lee Michelle P. , Lagisetty Kiran H. , Lin Jules , Reddy Rishindra M. , Chang Andrew C. , Howell Amy B. , Kresty Laura A. 
Published: April 2023

Esophageal adenocarcinoma (EAC) is the major subtype of esophageal cancer in Westernized countries, characterized by rising incidence and poor prognosis with a five-year survival rate less than 20%. Only 15% of EAC patients have a complete histopathological response to standard chemotherapy, indicating the urgent need to identify mechanisms associated with therapeutic resistance for improved therapeutic efficacy and patient outcomes. Herein, we performed transcriptional profiling utilizing tissues collected from EAC patients prior to treatment initiation. First, EAC patients (n=67) were stratified into 5 therapeutic response groups based on the changes in TNM pre- to post-treatment; second, bioinformatic approaches were utilized to identify molecular changes associated with response to treatment and patient survival. Third, we employed OE19 and OE33 human EAC cell lines to investigate the efficacy of cranberry proanthocyanidins (C-PAC), a promising anti-inflammatory and anti-cancer agent which shows synergistic effects with carboplatin in other cancer types, at mitigating molecular pathways which drive therapeutic resistance. Our therapeutic response data set revealed epithelial-mesenchymal transition (EMT) as a top pathway associated with differential response to therapy and patient survival. Subsequent gene-set enrichment analysis identified that EMT is significantly associated with NFκB and STAT3 signaling pathways, two nodes with documented proinflammatory roles in EAC progression. Deconvolution analysis was conducted further supporting EMT enrichment creates an immune-suppressive tumor microenvironment in EAC patients. Next, EAC cell viability, migration and interrogation of EMT signaling proteins were conducted following treatment with paclitaxel and carboplatin (chemo drugs) alone or in combination with C-PAC. Combination treatment of C-PAC and chemo drugs significantly inhibited EAC cell viability and migration capability, compared to cells treated with chemo drugs alone, with synergistic effects observed in OE33 cells. Moreover, combination treatment also significantly decreased NFκB1 expression and expressions of EMT markers and transcription factors (Snail, MMP-2, MMP-9, and Vimentin) whereas cells treated only with chemo drugs showed minimal modulation. Knockdown experiments of NFκB1 using RNA interference are underway to investigate the relationship between canonical NFκB1 signaling and EMT. Primary cell lines and organoids developed from isolated EAC patient tissues will also be used in the future to validate experimental findings. The results suggest C-PAC may be used as a safe and novel therapeutic strategy to improve chemotherapy efficacy targeting EAC.

Citation Format: Yun Zhang, Katherine M. Weh, Connor L. Howard, Jean-Jack Riethoven, Jennifer L. Clarke, Michelle P. Lee, Kiran H. Lagisetty, Jules Lin, Rishindra M. Reddy, Andrew C. Chang, Amy B. Howell, Laura A. Kresty. Targeting therapeutic resistance of esophageal adenocarcinoma through modulating the epithelial-to-mesenchymal transition via NFκB-mediated signaling [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 1745.