Abstract 1710: Advancing HER2-targeted ADC drug discovery through resistant cell line generation and cancer cell panel analysis

Abstract Antibody-drug conjugates (ADCs) represent a cutting-edge class of targeted cancer therapeutics, seamlessly integrating the high specificity of monoclonal antibodies with the cytotoxic power of chemotherapy agents. This strategic union facilitates the precise delivery of a potent cytotoxic payload to HER2-expressing cancer cells, where HER2 is a well-established therapeutic target. Despite the promising efficacy of HER2-directed ADCs in treating HER2-positive breast cancer, the emergence of resistance in tumor cells poses a significant obstacle to their therapeutic potential. The present study is designed to meticulously assess the anti-tumor efficacy of HER2-targeted ADCs across a diverse panel of cancer cell lines exhibiting varying levels of HER2 expression. Furthermore, to delve into the complexities of resistance, we have developed in vitro models of resistance by subjecting cells to cyclical exposure to DS-8201, a leading HER2-targeted ADC, and its payload, Dxd. Our findings reveal a pronounced inhibitory effect of HER2-targeted ADCs on HER2-positive cancer cell lines, underscoring their selective cytotoxicity. A critical insight from our research is the observation of a significant reduction in HER2 protein levels in cell lines that have developed resistance. This decrease is hypothesized to be a key factor in the resistance mechanism, potentially by limiting the availability of the target for ADC binding. The elucidation of these resistance mechanisms is pivotal, as it informs the strategic development of next-generation HER2-targeted therapies. By addressing the issue of resistance, we aim to enhance the efficacy of HER2-targeted treatments and ultimately improve patient outcomes in the battle against breast cancer. Citation Format: Lili Chai, Taotao Cao, Xue Yang, Wei Liu, Zhengtai Li, Xiaojian Wang, Tj (Tiejun) Bing. Advancing HER2-targeted ADC drug discovery through resistant cell line generation and cancer cell panel analysis [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 1710.