Abstract 536: Breaking through ADCs resistance: Constructing preclinical enhertu-induced resistant model

Abstract Antibody-drug conjugates (ADCs) are compounds that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxic payload of toxic substances. In recent years, ADCs have rapidly developed in the field of cancer therapy, particularly in the treatment of HER2-positive breast cancer. One representative example is Trastuzumab deruxtecan (Enhertu), which has become a new benchmark for anti-HER2 ADCs due to its excellent performance in clinical trials. Despite the impressive clinical outcomes of ADCs, some tumors in patients may still develop resistance to these drugs. Therefore, it is crucial to understand the mechanisms of resistance and develop strategies to overcome ADCs resistance. To achieve these goals, it is essential to establish and utilize preclinical models to study these resistance mechanisms. Preclinical models of resistance to ADCs have mainly been generated using human cultured cell lines. JIMT-1 is a HER2-positive breast cancer cell line that exhibits primary resistance to the anti-HER2 antibody trastuzumab and also shows resistance to trastuzumab-derived ADC T-DM1. However, we found that Enhertu significantly inhibited tumor growth in JIMT-1 xenograft models. We subjected JIMT-1 tumor tissues to continuous passage in mice and administered long-term drug induction. The tumor growth rate gradually increased, and the drug sensitivity decreased, resulting in the acquisition of an Enhertu-resistant tumor model. The obtained resistant tumor tissues not only include tumor cells themselves but also comprise fibroblasts, extracellular matrix, and other cellular components, enabling a more comprehensive investigation into the interactions between different cells within the tumor microenvironment (TME). We believe that the establishment of preclinical Enhertu-resistant models helps predict resistance that has not yet emerged clinically and provides references for future drug development. Citation Format: Yuan Fang, Huiyi Wang, Jun Xing, Lu Yang, Jing Zhao, Xiang Gao, Cunxiang Ju. Breaking through ADCs resistance: Constructing preclinical enhertu-induced resistant model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 536.