WCLC 2025 - Posters & ePosters-PT1.02.03 GBC-11004: An AI-Driven Novel Kinase Target With Potential to Overcome Osimertinib Resistance in NSCLC

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This study presents an AI-driven platform developed by Gradiant Bioconvergence Inc. for identifying novel therapeutic targets to overcome Osimertinib resistance in non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR inhibitor, faces clinical challenges due to resistance mechanisms in NSCLC patients. Traditional next-generation sequencing (NGS) methods often fail to pinpoint actionable targets because of tumor heterogeneity. The platform integrates three AI components: G-TAC (deep learning prediction), G-SET (statistical testing), and G-LAT (literature-based novelty analysis) to systematically identify and rank potential targets from patient-derived organoids (PDOs) exhibiting Osimertinib resistance.<br /><br />Using this approach, a novel kinase target, GBC-11004, was identified as highly overexpressed in resistant PDOs. Functional validation through CRISPR/Cas9-mediated gene knockout—delivered via a doxycycline-inducible lentiviral system—demonstrated efficient editing (indel rates 49-92%), sustained suppression of GBC-11004 protein, reduced cell viability, and increased apoptosis in multiple Osimertinib-resistant PDO lines. The gene knockdown effects were significant in reducing tumor cell viability and inducing apoptosis, indicating therapeutic potential.<br /><br />Further, combination treatment of Osimertinib with a novel kinase inhibitor targeting GBC-11004 (GBC-11004-001) markedly enhanced sensitivity in resistant PDOs carrying EGFR mutations (exon 19 deletions and L858R). The combination consistently decreased IC50 values relative to Osimertinib alone, while monotherapy with GBC-11004-001 also showed efficacy in certain PDOs. These results suggest that targeting GBC-11004 can restore or enhance Osimertinib response in resistant NSCLC.<br /><br />In conclusion, this AI-driven platform offers a novel approach to discovering therapeutically relevant targets to counteract drug resistance. GBC-11004 emerges as a promising target to overcome Osimertinib resistance in NSCLC, providing a foundation for new combination treatment strategies to improve clinical outcomes in advanced lung cancer.

Asset Subtitle

Jihye Ryu

Meta Tag

Speaker Jihye Ryu

Topic Tumor Biology – Preclinical Biology

Keywords

AI-driven platform

Osimertinib resistance

non-small cell lung cancer

Gradiant Bioconvergence Inc.

GBC-11004 kinase target

patient-derived organoids

CRISPR/Cas9 gene knockout

combination therapy

EGFR mutations

drug resistance mechanisms