临床可预测的患者来源细胞和类器官平台用于NSCLC的精准治疗评估

Purpose : Patient-derived cells (PDCs) and organoids (PDOs) are established from pleural effusion or ascites to recapitulate the biological features of individual patients. In cancer research, PDC/PDOs serve as valuable preclinical tools because they preserve tumor-specific mutations. Conventional cell lines often fail to capture resistance mechanisms to modern targeted therapies. Consequently, PDC/PDOs offer robust systems for predicting the efficacy of next-generation anticancer treatments. This study aims to demonstrate that PDC/PDO lines serve as suitable platforms for evaluating the efficacy of investigational therapeutics and screening novel therapies for non-small cell lung cancer (NSCLC). Experimental design : PDC/PDO models were generated from malignant pleural effusions or ascites, using only cytologically confirmed specimens that formed tumor colonies. Genomic alterations were profiled by Sanger sequencing, Whole-exome sequencing (WES), or RNA sequencing. Drug responses were evaluated according to each patient's treatment history to directly compare clinical outcomes with ex vivo sensitivity. Results : A total of 60 PDCs and 181 PDOs were established from NSCLC patients, including models harboring sensitizing EGFR mutations, KRAS mutations, uncommon mutations, ALK fusions, ROS1 fusions, EGFR exon 20 insertion, and BRAF V600E. Whole-exome sequencing (WES) was performed on 41 newly established NSCLC PDO lines to characterize their genomic alterations. The analysis revealed that EGFR alterations in the PDO cohort comprised 29 amplifications, 20 missense mutations (including L858R, T790M, G719X, C797S, and other mutations), 9 in-frame deletions (E19del), and 1 in-frame insertion (E20ins). Furthermore, MET alterations included 16 amplifications and 1 loss, while ERBB2 exhibited 6 amplifications and 1 in-frame insertion. In three newly established BRAF V600E-mutant PDC models (YU-1171, YU-1172, and YU-1195), exposure to the targeted agents dabrafenib and trametinib revealed distinct patterns of drug sensitivity. The IC 50 values for dabrafenib and trametinib in YU-1171 were 31.2 nM and 2.96 nM, respectively. In YU-1172, the IC 50 for dabrafenib exceeded 1 μM, whereas that for trametinib was 14.2 nM. In YU-1195, the corresponding IC 50 values were 438.4 nM and 10.9 nM. These in vitro trends were concordant with clinical outcomes, as the duration of dabrafenib and trametinib treatment in the corresponding patients was significantly associated with the respective IC 50 profiles. Conclusions : Clinically matched patient-derived cells and organoids reliably recapitulate tumor characteristics, providing a robust ex vivo platform for precision therapeutic evaluation in NSCLC.