Despite the widespread utilization of Patient-Derived Xenografts (PDXs) as preclinical platforms in lung cancer research, there are concerns regarding their capability to accurately represent the tumor's clinical and molecular features across sequential passages. In this study, we established a Non-Small Cell Lung Cancer (NSCLC) PDX model in NSG-SGM3 mice and assessed clinical and preclinical factors throughout subsequent passages. Our cohort consisted of 40 NSCLC patients, which were used to successfully create 20 patient-specific PDX models in NSG-SGM3 mice. We found that the main factors that contributed to the growth of the engrafted PDX in mice were a higher grade or stage of disease, in contrast to a long duration of chemotherapy treatment which was negatively correlated with PDX propagation. Successful PDX growth was also linked to poorer prognosis and overall survival, while growth pattern variability was affected by the tumor's aggressiveness, primarily affecting the first passage. Pathology analysis showed preservation of histological type and grade; however, Whole Exome Sequence (WES) analysis revealed genomic instability in advanced passages, leading to the inconsistency of clinically relevant alterations between PDXs and biopsies. Multiple clinical and preclinical factors affect the engraftment success, growth kinetics, and tumor stability of patient-specific NSCLC PDXs; thus, their use for prolonged treatment evaluation studies remains questionable.
