WRN Inhibitors(AbbVie)

Cancer cell line profiling can offer key insights into drug activity, target dependency and resistance pathways. At the AACR Annual Meeting in San Diego coming week, we will present new large‑scale profiling data on trophoblast cell surface antigen 2 (TROP2)‑targeting ADCs. Moreover, insights into predictive biomarkers for two WRN inhibitors, as well as combination strategies to overcome resistance to KRASG12C inhibitors, will be presented. TROP2 is highly expressed across epithelial tumors, making it an attractive ADC target. Sacituzumab govitecan (Trodelvy®) was approved by the FDA in 2020 for triple‑negative breast cancer (TNBC), but its short plasma half‑life urged the development of more stable alternatives. Sacituzumab tirumotecan (sac‑TMT) and datopotamab deruxtecan (Dato‑DXd, Datroway®) are newer TROP2‑directed ADCs, each carrying a topoisomerase‑1 inhibitor with a distinct antibody and linker design. Both ADCs were FDA-approved in 2025 for EGFR-mutated NSCLC and for HR+/HER2– breast cancer independently of tumor TROP2 levels. This indicates that TROP2 expression alone is insufficient to predict clinical benefit and highlights the need for additional predictive biomarkers. At the AACR Annual Meeting, we will present cell panel profiling data for Dato‑DXd and sac‑TMT across 270 cancer cell lines. Despite sharing the same target and payload class, the two ADCs display distinct response profiles. Dato‑DXd shows sensitivity in only a limited subset of cell lines, whereas sac‑TMT demonstrates activity across a broad range of cell lines. Bioinformatics analyses further identified genes whose expression strongly correlated with ADC sensitivity, providing additional insight into potential predictive biomarkers. In addition, comparative analyses of ADC sensitivity profiles against those of 249 reference inhibitors were performed to identify agents with the most similar response patterns. Finally, liver enzyme stability assays were conducted to evaluate the chemical stability of the ADCs. Oncolines B.V. is a precision medicine services company in oncology and cancer immunotherapy. Oncolines is part of the Symeres group of companies, a group of high-quality CROs and CDMOs based in Europe and the United States.