Abstract 1714: Understanding ADC resistance using preclinical enhertu-induced resistant models

Abstract Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies (mAbs) with potent cytotoxic payloads, offering a promising approach for targeted cancer therapy. Enhertu (trastuzumab deruxtecan, DS-8201), an ADC targeting HER2-positive cancers, has demonstrated remarkable efficacy in clinical settings, setting new benchmarks for anti-HER2 ADCs. However, drug resistance remains a significant challenge, underscoring the need to elucidate resistance mechanisms and develop strategies to overcome them. To address this important question, we established a robust preclinical platform to study Enhertu resistance by subjecting HER2-positive JIMT-1 xenograft tumors to a series of in vivo passaging and drug induction. Massive parallel sequencing analyses, including RNA sequencing (RNA-Seq) and whole-exome sequencing (WES), revealed multiple resistance-associated pathways, with a particular emphasis on payload-resistance mechanisms. Flow cytometry and IHC analyses confirmed no significant changes in HER2 expression levels between resistant and parental tumors, ruling out target downregulation as the main resistance mechanism. Notably, the resistant tumor provided a valuable platform for studying interactions within the tumor microenvironment (TME), including stromal and immune components that may contribute to resistance development. The establishment of these preclinical Enhertu-resistant models offers a unique opportunity to investigate resistance mechanisms that may not yet be observed in clinics. Furthermore, these models provide a foundation for testing innovative therapeutic strategies, such as combination treatments targeting multiple pathways or the development of next-generation ADCs with improved payload efficacy. By enhancing our understanding of ADC resistance, these findings contribute to the advancement of personalized cancer therapies and may ultimately improve outcomes for patients with HER2-positive malignancies. Citation Format: Hongyan Sun, Yuan Fang, Fang Zhu, Jianming Xu, Xiang Gao, Jun Wang. Understanding ADC resistance using preclinical enhertu-induced resistant models [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 1714.