Abstract 3307: Utilizing endocytosis as a predictive biomarker for ADCs

Abstract Antibody drug conjugates (ADCs) consist of an antibody conjugated to a chemotherapeutic drug. These therapeutic compounds are designed to exert improved targeted toxicity as compared to conventional chemotherapy. However, variable therapeutic outcome has been experienced and predictive markers for response are warranted. ADCs are dependent on endocytosis to exert their effect, and we have hypothesized that proteins regulating the endocytic machinery can be utilized as predictive biomarkers. We have shown, for the first time, that the expression level of Rab5A, a protein regulating endocytosis correlates to the efficacy of Trastuzumab Emtansine, a HER2 targeted ADC. Furthermore, we have documented Rab5A as a predictive biomarker for Trastuzumab emtansine in three independent clinical cohorts. We are currently investigating the interplay between different ADCs and the endo/lysosomal machinery, and aim to develop this concept to a diagnostic tool for patients to be treated with ADCs. We use Trastuzumab emtansine, Trastuzumab deruxtecan and Sacituzumab Govitecan as model ADCs and evaluate the impact of different Rab GTPases on their mechanism of actions in cell lines from breast- and lung-cancer. Citation Format: Anette Weyergang, Astrid Medhus, Kay Oliver Schink, Kristian Berg, Olav Engebraaten. Utilizing endocytosis as a predictive biomarker for ADCs [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 3307.