Patient-derived non-small cell lung cancer xenograft mirrors complex tumor heterogeneity.

Objective: Patient-derived xenograft (PDX) models have shown great promise in preclinical and translational applications, but theirconsistency with primary tumors in phenotypic, genetic, and pharmacodynamic heterogeneity has not been well-studied. This studyaimed to establish a PDX repository for non-small cell lung cancer (NSCLC) and to further elucidate whether it could preserve theheterogeneity within and between tumors in patients. Methods: A total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice. Based on thesuccessful establishment of the NSCLC PDX model, we compared the expressions of vimentin, Ki67, EGFR, and PD-L1 proteins betweencancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining. In addition, we detectedwhole gene expression profiling between primary tumors and PDX generations. We also performed whole exome sequencing (WES)analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities. Finally, paclitaxel, cisplatin,doxorubicin, atezolizumab, afatininb, and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents. Results: A large collection of serially transplantable PDX models for NSCLC were successfully developed. The histology andpathological immunohistochemistry of PDX xenografts were consistent with the patients’ tumor samples. WES and RNA-seq furtherconfirmed that PDX accurately replicated the molecular heterogeneities of primary tumors. Similar to clinical patients, PDX modelsresponded differentially to the standard-of-care treatment, including chemo-, targeted- and immuno-therapeutics. Conclusions: Our established PDX models of NSCLC faithfully reproduced the molecular, histopathological, and therapeuticcharacteristics, as well as the corresponding tumor heterogeneities, which provides a clinically relevant platform for drug screening,biomarker discovery, and translational research.