Abstract 1702: OBI-992, a novel TROP2 antibody-drug conjugate, exhibits distinct resistance profiles compared to other TROP2 targeting ADCs

Abstract BACKGROUND/AIM: Trophoblast cell surface antigen-2 (TROP2), a transmembrane glycoprotein often overexpressed in a variety of cancers, has been proposed as a potential cancer driver in colorectal cancer (CRC) cells. As a result, several antibody-drug conjugates (ADC) have been developed targeting TROP2, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-Dxd). One of the major challenges in the development of ADC is the emergence of resistance via different mechanism of actions. This study aims to characterize the potential resistant mechanisms of TROP2 ADCs, including a novel TROP2 ADC OBI-992 in CRC cells. METHODS: DLD1 CRC cells resistant to OBI-992, SG, and Dato-Dxd analogs were established with sequential increase of respective ADC concentrations. Cytotoxicity of three ADCs and their payloads, including exatecan, SN-38, and Dxd, was evaluated to assess the fold of resistance. Cell surface and total TROP2 protein were measured by flow cytometry and western blotting. DNA mutation and gene expression profiling were conducted by whole exome sequencing (WES) and RNA sequencing (RNA-seq). RESULTS: TROP2 reduction and multidrug resistance proteins (MRPs) enhancement were not detected in OBI-992-induced resistant cells. Notable different DNA mutations in ATRX, BRCA2, and PALB2 of OBI-992 resistant cells were detected compared to those found with Dato-Dxd and SG-selected resistant cells. A TOP1 inhibitor-resistant mutation, TOP1 R364H, was identified as 100% variant allele frequency (VAF) in Dato-Dxd and SG resistant cells, whereas lower percentage of VAF was observed in OBI-992 resistant cell lines (29 % and 48.6 % in 0.5 uM and 2uM of OBI-992, respectively). OBI-992 resistant cells showed a clear divergence in differential expression gene (DEG) profiles, whereas Dato-Dxd and SG resistant cells were similar. c-MET and REG4 levels were greatly increased in cells with Dato-Dxd and SG resistance but not with OBI-992. Extracellular matrix (ECM) receptor interaction pathway was enriched in OBI-992 resistant cells. CONCLUSION: OBI-992, a novel TROP2 targeting ADC, emerges as a potential promising therapeutic option for patients who are resistant to other TROP2 targeting ADCs such as SG and Dato-Dxd. OBI-992 exhibits distinct resistance profiles compared to other TROP2 targeting ADCs. Understanding of potential mechanisms of resistance can provide potential combination options for TROP2-targeting ADCs to combat the drug resistance. Citation Format: Lifen Shen, Tzer-Min Kuo, Yu-Hsuan Tsao, Ya-Chi Chen, Ming-Tain Lai. OBI-992, a novel TROP2 antibody-drug conjugate, exhibits distinct resistance profiles compared to other TROP2 targeting 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 1702.