Abstract 6885: Plectin as a novel therapeutic target for pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 3rd deadliest cancer in the United States with only a 5-year survival rate of 13%, demonstrating a desperate need for novel therapeutic targets to significantly enhance options for patients. In 2008, Kelly et al. pioneered a phage-display-based functional-proteomic approach and identified a cytolinker protein, plectin, which was mislocalized and ubiquitously expressed on the membrane of PDAC. This unique localization of plectin, called cell surface plectin (CSP), has since been found to be expressed on the cell surface of many cancer subtypes, including PDAC, ovarian carcinoma and cholangiocarcinoma, but remains cytoplasmic in normal tissues. Knockdown of plectin and an anti-CSP functional monoclonal antibody revealed the importance of CSP to proliferation, migration, and invasion in cancers. Recently, a phase 1 clinical trial using an anti-CSP antibody, ZB131 (NCT05074472) in CSP positive cancer subtypes showed ZB131 as a viable and safe drug candidate for treatment. In the trial, treatment with ZB31 led to stable disease in 3 out of 9 PDAC patients. In order to more fully understand the mechanism of action of ZB131 and to obtain comprehensive understanding of molecular signaling of CSP in cancer we have employed bioinformatic strategies as well as knock outs using CRISPR/Cas9 inducible systems. Transcriptomic data from bulk and single cell RNA-seq data from human PDAC revealed that CSP overexpressing tumors were enriched for integrin-extracellular matrix interactions, suggesting CSP plays a major role in matrix remodeling and metastasis. Additionally, treatment with anti-CSP antibody led to a decrease in classic signaling cascades associated with cancer progression such as SRC, PRAS40, STAT3, AKT, and ERK1/2. The cumulative work from this research highlights the role of CSP in PDAC and suggests a desperate need for an anti-CSP therapeutic for patients. Citation Format: Cody L. Wolf, Roxanne K. Ruiz, Julien Dimastromatteo, Samantha Perez, Matthew J. Reilley, Kimberly A. Kelly. Plectin as a novel therapeutic target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6885.