Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation

Han Na Kang, Jae Woo Choi, Hyo Sup Shim, Jinna Kim, Dae Joon Kim, Chang Young Lee, Min Hee Hong, Seong Yong Park, A. Young Park, Eun Joo Shin, Seo Yoon Lee, Kyoung Ho Pyo, Mi Ran Yun, Hun Mi Choi, Sung Sook Lee, Seok Young Kim, Hanna Lee, Soonmyung Paik, Byoung Chul Cho, Jin Gu LeeHye Ryun Kim

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Abstract

Background: Preclinical models that can better predict therapeutic activity in clinical trials are needed in this era of personalized cancer treatment. Herein, we established genomically and clinically annotated patient-derived xenografts (PDXs) from non-small-cell lung cancer (NSCLC) patients and investigated whether these PDXs would faithfully recapitulate patient responses to targeted therapy. Methods: Patient-derived tumors were implanted in immunodeficient mice and subsequently expanded via re-implantation. Established PDXs were examined by light microscopy, genomic profiling, and in vivo drug testing, and the successful engraft rate was analyzed with the mutation profile, histology, or acquisition method. Finally, the drug responses of PDXs were compared with the clinical responses of the respective patients. Results: Using samples from 122 patients, we established 41 NSCLC PDXs [30 adenocarcinoma (AD), 11 squamous cell carcinoma (SQ)], among which the following driver mutation were observed: 13 EGFR-mutant, 4 ALK-rearrangement, 1 ROS1-rearrangement, 1 PIK3CA-mutant, 1 FGFR1-amplification, and 2 KRAS-mutant. We rigorously characterized the relationship of clinical features to engraftment rate and latency rates. The engraft rates were comparable across histologic type. The AD engraft rate tended to be higher for surgically resected tissues relative to biopsies, whereas similar engraft rates was observed for SQ, irrespective of the acquisition method. Notably, EGFR-mutants demonstrated significantly longer latency time than EGFR-WT (86 vs. 37days, P = 0.007). The clinical responses were recapitulated by PDXs harboring driver gene alteration (EGFR, ALK, ROS1, or FGFR1) which regressed to their target inhibitors, suggesting that established PDXs comprise a clinically relevant platform. Conclusion: The establishment of genetically and clinically annotated NSCLC PDXs can yield a robust preclinical tool for biomarker, therapeutic target, and drug discovery.

Original languageEnglish
Pages (from-to)168-178
Number of pages11
JournalLung Cancer
Volume124
DOIs
Publication statusPublished - 2018 Oct

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Kang, H. N., Choi, J. W., Shim, H. S., Kim, J., Kim, D. J., Lee, C. Y., Hong, M. H., Park, S. Y., Park, A. Y., Shin, E. J., Lee, S. Y., Pyo, K. H., Yun, M. R., Choi, H. M., Lee, S. S., Kim, S. Y., Lee, H., Paik, S., Cho, B. C., ... Kim, H. R. (2018). Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation. Lung Cancer, 124, 168-178. https://doi.org/10.1016/j.lungcan.2018.08.008