ICE Bioscience Posters

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The DNA Damage Response (DDR) pathway is the core biological system through which cells detect and repair genomic lesions. Targeting DDR pathways and inhibiting DNA repair mechanisms has emerged as a highly promising strategy in cancer therapy, with significant breakthroughs achieved in the development of DDR inhibitors. Antibody-drug conjugates (ADCs)—which combine the precise targeting of antibodies with the potent cytotoxicity of drugs—represent a promising antineoplastic therapy. However, current ADCs face critical challenges, including non-responsive cancers, drug resistance, and rapid patient relapse, primarily driven by tumor heterogeneity and resistance. To address these issues, dual-payload ADCs have emerged as an innovative strategy: they deliver two cytotoxic agents to enhance efficacy via synergistic effects, mitigate resistance, and enable flexible dosing. Despite their potential, dual-payload ADC development remains complex; cell panel-based studies and drug-resistant cell lines serve as powerful tools to explore effective dual-payload ADCs by evaluating drug combination synergies and elucidating resistance mechanisms. To advance the development of DDR pathway-based dual-payload ADCs, this study leveraged an in-house DDR platform to conduct large-scale synergy screening in ADC-resistant cell lines. The screening panel included over 120 targeted molecules and chemotherapeutics, covering DDR core pathway proteins (e.g., WRN, PARP, ATR, DNAPK), cell cycle regulators, and kinase families such as tyrosine kinases. Screening results revealed that ATR inhibitors combined with Topoisomerase I (TOPO1) inhibitors exhibit strong synergistic activity; their specific molecular mechanisms require further validation. This optimal combination provides a direct candidate for DDR pathway-targeted dual-payload ADC development, with the potential to accelerate the research, development, and translation of next-generation DDR-enabled ADC modalities.