Abstract LB069: An agrin mechanotransduction for EGFR-addicted cancers

Abstract Epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), where it senses extracellular matrix (ECM) rigidity. Despite our understanding of the increasing role of tissue rigidity on various hallmarks of cancer development, how the ECM-driven mechanotransductive network impacts EGFR-dependent tumorigenesis remains uncharacterized. Here we show that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR-driven mouse models, and human specimens. The agrin expression confers substrate stiffness-dependent oncogenic attributes to EGFR-reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)-dependent and independent modes, thereby sensitizing its activity toward localized cancer cell-ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed-forward loop linking agrin-EGFR rigidity response to YAP-TEAD mechanosensing is essential for tumorigenesis. Together, we propose that the combined inhibition of EGFR-YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin-EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR-addicted lung cancers. Citation Format: Sayan Chakraborty. An agrin mechanotransduction for EGFR-addicted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB069.