Abstract 2952: The oncomucin MUC4 EGF domains: A new paradigm to target ErbB/HER and RTK receptors in pancreatic adenocarcinoma using inhibitory small molecules

Abstract Pancreatic adenocarcinoma is one of the deadliest cancers with an increasing incidence. It is mainly due to absence of diagnosis and no effective treatments, and a strong resistance to therapies. It is thus crucial for this devastating cancer to find new therapeutic alternatives. In this aim, we work on the interaction of the mucin MUC4 with receptor tyrosine kinases (RTK), and the targeting of MUC4 using small inhibitory molecules. MUC4, a large glycoprotein overexpressed at the surface of pancreatic cancer cells, is associated with poor prognosis of the tumor, increase of proliferation and migration as well as apoptosis and resistance to therapies. Moreover, we have shown that MUC4EGF domains interact with and upregulates the activity of ErbB2/HER2, this complex being a strong promoter of tumorigenesis. Use of small inhibitory molecules would circumvent the steric hindrance played by MUC4 glycosidic chains. We have now, using molecular dynamics and peptide library screening, identified a specific MUC4EGF domain inhibitory peptide (i) capable of inhibiting MUC4-ErbB2 complex formation and activity, (ii) having anti-proliferative activity and (ii) resensitizing pancreatic cancer cells to Trastuzumab and Pertuzumab ErbB2-targeted therapies.During these studies, we also observed that MUC4 interaction with ErbB2 led to the activation of the other members of the ErbB/HER family as well as other RTKs showing structural similarities with the ErbB/HER family. Our hypothesis is thus that MUC4 may play the role of an oncogenic interaction platform at the surface of pancreatic cancer cells. The interactions between MUC4 and the ErbB/HER family, Met, Axl, EpCAM, and IGF-1R were studied and characterized using Proximity Ligation Assay, MicroScale Thermophoresis, co-immunoprecipitation, GST pull-down. Our results show that MUC4 interacts directly via its EGF domains with and activate ErbB1,3,4, Met, Axl, IGF-1R and EpCAM. These interactions (i) are independent of ErbB2 expression and (ii) activate downstream oncogenic signaling pathways to maintain proliferation and migration capacities of pancreatic cancer cells. At this time, other drugs (tyrosine kinase inhibitors, mAbs) are currently being screened in association with our MUC4 inhibitory peptide to find the best therapeutic combination possible. Taken together, these results provide new paradigms on the inhibitory small molecule-based therapeutics targeting of ErbB/HER and RTK receptors as partners of the oncomucin MUC4 in pancreatic cancer but also in all epithelial cancers overexpressing these complexes. Citation Format: Tristan Girgin, Nicolas Stoup, Elsa Faillon, Maxime Liberelle, Nicolas Lebegue, Isabelle Van Seuningen. The oncomucin MUC4 EGF domains: A new paradigm to target ErbB/HER and RTK receptors in pancreatic adenocarcinoma using inhibitory small molecules [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 2952.