AACR 2026 Poster 4449

Functional Organoid Screening Uncovers Target Dependency and Bystander Killing in TROP2 ADCs

Jialei Sun, Marten Hornsveld, Linda Xue, Lenno Krenning, Dorrith Verstegen, Peng Han, Zhongman Sun, Caitlyn Hulsebosch, Dione Blok, Peter van Schaik, Mali He, Huike Ju, Yi Sun, Mariusz Madej, Hester Bange, Jun Zhou, Peng Wang, Ludovic Bourre, Marrit Putker

Discover how large-scale patient-derived organoid screening combined with CRISPR engineering and 3D high-content imaging enables comprehensive evaluation of TROP2-targeted ADC efficacy and mechanisms.

Reliable antibody-drug conjugate (ADC) evaluation requires models that accurately reflect human target expression, cellular signaling, and DNA damage responses. This study demonstrates how patient-derived organoids (PDOs) provide a physiologically relevant platform to assess TROP2 ADCs including datopotamab–deruxtecan. By combining functional screening across over 100 tumor models with CRISPR-generated resistance pairs and advanced imaging, this approach enables precise dissection of target dependency, payload resistance, ADC uptake dynamics, and bystander killing effects—delivering actionable insights for ADC optimization and clinical development.

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• Screen ADC efficacy across diverse patient contexts: Evaluate TROP2 ADC responses across 109+ patient-derived organoid models spanning ten cancer types, revealing tumor-type specific sensitivity patterns.
  
  
• Validate target dependency with CRISPR models: Use isogenic TROP2 knockout organoid pairs to definitively confirm on-target activity and distinguish target-dependent from payload-level resistance.
  
  
• Visualize ADC uptake and payload mechanism: Leverage high-content imaging to track antibody penetration dynamics, DNA damage marker accumulation, and payload-specific mode-of-action in 3D.
  
  
• Assess correlation between TROP2 expression and response: Explore how target mRNA abundance relates to ADC efficacy using growth rate inhibition metrics and dose-response analysis.
  
  
• Model bystander effects in heterogeneous cultures: Quantify payload-mediated bystander killing using mixed wild-type and TROP2-KO organoid co-cultures that mimic tumor heterogeneity.
  
  
• Compare payloads and linker strategies: Benchmark topoisomerase I inhibitors (exatecan, DXd) against microtubule inhibitors and DNA-damaging agents to guide payload selection.

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