Development and Characterization of Patient-Derived Xenografts from Non-Small Cell Lung Cancer Brain Metastases


June 3, 2020

bioRxiv, Tempus-acknowledged —

Introduction: NSCLC brain metastasis cell lines and in vivo brain metastasis models are not widely
accessible. The purpose of this study was to establish and characterize a direct-from patientderived xenograft (PDX) model of non-small cell lung cancer (NSCLC) brain metastases.

Methods: Surgically obtained tissue was implanted subcutaneously and as orthotopic intracranial implants
into immunodeficient mice. Histology and DNA loci were compared between original tumor and
subsequent PDX passages. Tumors underwent RNA and DNA sequencing and relevant
therapeutic targets were identified. Tumor growth rates were assessed following treatment with
radiation, MEK inhibitor selumetinib, or MET inhibitor savolitinib. Cell lines were established.

Results: Nine NSCLC brain metastases PDXs were established. Morphologically, strong retention of
cytoarchitectural features was observed between original patient tumor and subcutaneous and
intracranial tumors. Preservation of thyroid transcription factor 1 expression was seen in all
xenografts. Short tandem repeat analysis demonstrated strong concordance between patient
tumors and subsequent PDX passages. RNA sequencing analysis revealed high correlation
between matched patient and PDX samples. Significant growth inhibition was shown with
radiation, with selumetinib in tumors harboring KRAS G12C mutation and with savolitinib in
tumors with MET exon 14 skipping mutation. Significant tumor growth delay was observed with
the combination of radiation and savolitinib compared to radiation or savolitinib alone in the PDX
harboring MET exon 14 skipping mutation. Early passage cell strains showed high consistency
between patient and PDX tumors.

Conclusion: We have established a robust human xenograft model system for investigating NSCLC brain
metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with
the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

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Authors: Andrew M. Baschnagel, Saakshi Kaushik, Arda Durmaz, Steve Goldstein, Irene M. Ong, Lindsey Abel, Paul A. Clark, Ticiana Leal, Darya Buehler, Gopal Iyer, Jacob G. Scott, Randall J. Kimple