Abstract 3821: Berberine and emodin synergistically suppress the EGFR signaling cascade by targeting LAMB3 in pancreatic ductal adenocarcinoma

Abstract

Abstract Background: Pancreatic cancer is one of the most devastating malignancies due to the development of intrinsic chemoresistance following chemotherapy. Extracellular matrix (ECM) proteins are intimately linked to cellular proliferation, invasion, and acquisition of chemoresistance in PDAC cells, making them promising therapeutic targets in this malignancy. Naturally occurring dietary botanicals, including berberine (BER) and emodin (EMO), have been shown to suppress ECM as one of the mechanism(s) for their anti-tumorigenic activity, along with their time-tested safety and cost-effectiveness. In addition, both BER and EMO are also known to induce apoptosis by modulating different pathways and regulating pro-apoptotic genes. Herein, we hypothesized that combined treatment with BER and EMO might exhibit synergistic anticancer efficacy by targeting the ECM and apoptotic pathways in PDAC cells. Methods: We undertook genomewide transcriptomic profiling analysis to identify critical ECM-related genes differentially expressed in PDAC. Subsequently, the TCGA dataset was analyzed to identify the prognostic significance of ECM-associated genes with overall survival (OS) and disease-free survival (DFS) in PDAC. A series of cell culture experiments were performed using PDAC cells, followed by their validation in patient-derived organoids to examine the synergistic anti-proliferative and chemopreventive effects of BER and EMO against PDAC. Results: Transcriptomic profiling identified that LAMB3 expression was significantly upregulated in PDAC tissue (P < 0.01) and was significantly associated with poor OS and DFS in PDAC patients (P < 0.01). The combination of BER and EMO displayed superior synergistic anti-tumor potential in PDAC cells vs. individual compounds, as revealed by cell proliferation, clonogenicity, migration, and invasion assays. The combination of BER and EMO also altered the expression of key proteins involved in cellular apoptosis, epithelial-mesenchymal-transition, and EGFR/ERK//AKT growth factor signaling pathways. Finally, these findings were successfully validated in PDAC patient-derived 3D organoids. Conclusions: We provide the first evidence that combined treatment with berberine and emodin exerts synergistic anti-cancer activity in PDAC, primarily regulated through the LAMB3-mediated interaction with other members of the EGFR-signaling pathway. Citation Format: CAIMING XU, SILEI SUI, Keisuke Okuno, Silvia Pascual-Sabater, Cristina Fillat, Ajay Goel. Berberine and emodin synergistically suppress the EGFR signaling cascade by targeting LAMB3 in pancreatic ductal adenocarcinoma. [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 3821.