Development and characterization of a novel in vivo JIMT-1 DS8201a resistant model and its efficacy evaluation

Trastuzumab deruxtecan, marketed as Enhertu (DS-8201a) is a next generation HER-2 targeted Antibody-Drug Conjugate (ADC), that releases a topoisomerase inhibitor payload. As the Deruxtecan is membrane permeable it exhibits a strong bystander effect as it can diffuse into neighboring cells, killing antigen negative cells. Despite clinical success and reinvigorating ADC interest, acquired and primary resistance driven by tumor heterogeneity and genomic alterations remain a major consideration. To investigate tumor resistance mechanisms, we have established in house a DS8201a resistant JIMT-1 cell line and the corresponding in vivo tumor model. We have also acquired a primary resistant gastric cancer PDX model (GAX227M), and we have derived an organoid model (PDXO) from this PDX. Based on in vitro and in vivo screening, we have demonstrated significant resistance to DS8201a in all models. Furthermore, we have comprehensive whole-exome sequencing (WES) and RNA sequencing (RNA-seq) for the JIMT-1 DS8201a-resistant model that is currently undergoing bioinformatic analysis. Our preclinical toolbox is designed to help decipher resistance mechanisms and guide rational strategies to overcome ADC resistance. These insights will inform the development of next-generation ADC's and improve outcomes in HER-2 positive heterogenous tumors.