Abstract 5192: Next-generation NSCLC drug development powered by PDCs and PDOs: Mimicking real responses

Abstract Purpose: Patient-derived cells (PDCs) and organoids (PDOs) derived from pleural effusion or ascites closely mimic the biological characteristics of individual patients. In cancer research, PDCs and PDOs serve as powerful tools for replicating tumor-specific mutations, overcoming the limitations of traditional cell lines, which fail to capture the heterogeneity and complexity of human tumors. Due to their ability to predict preclinical drug efficacy more accurately, PDCs and PDOs are increasingly utilized in therapy development. This study aims to demonstrate the potential of PDCs and PDOs as effective platforms for screening novel therapeutic strategies for non-small cell lung cancer (NSCLC). Experimental design: Malignant effusions were samples were tested for malignancy, processed, observed by light microscopy, and cultured. The establishment of a PDC was considered complete when it was free of normal cells, maintained known patient tumor mutation, and recapitulated patient’s response. Also, mutations that cell harbors are confirmed by Sanger sequencing, Whole exome sequencing, or RNA-sequencing. Results: Total of 54 PDCs and 171 PDOs were established from NSCLC patients, including models harboring various EGFR, KRAS and BRAF mutations and EML4-ALK or ROS1-CD74 fusions. Particularly the 8 models of PDC and 7 models of PDO harbor mutations which are well known for resistance mechanisms to EGFR-TKIs (T790M, C797S/C797G, MET amplification). Also, some models of PDCs were harboring uncommon EGFR mutations(EGFR G719S, L861Q, S768I etc.).For example, YUO-139 and YU-1092 are patient derived models that harbors uncommon EGFR mutation G719S and L861Q respectively. The models response to afatinib sensitively. IC50 of YUO-139 and YU-1092 to afatinib were 2.1 nM and 23.8 nM respectively. These models were evaluated for novel strategies for targeting uncommon EGFR mutations. Another example is YUO-143, which harbors EGFR mutations E19del/T790M/C797S and was derived from a patient resistant to gefitinib and mavelertinib. YUO-143 was used in the development of the 4th gen TKI, BLU-945, and showed an IC50 of 43 nM. Conclusions: Patient-derived models could serve as a crucial tool in developing novel therapeutic strategies and next-generation drugs for NSCLC. Citation Format: Sewon Park, Min Hak Lee, Ju-hyeon Lee, Mi Ran Yun, Min Hee Hong, Sun Min Lim, Jii Bum Lee, Byoung Chul Cho. Next-generation NSCLC drug development powered by PDCs and PDOs: Mimicking real responses [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 5192.