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Abstract
Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC brain metastases with genomic annotation useful for translational and mechanistic studies. Both heterotopic and orthotopic intracranial xenografts were established and RNA and DNA sequencing was performed on patient and matching tumors. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples with more than more than 95% of variants detected being retained in the matched PDXs. PDXs demonstrated response to radiation, response to selumetinib in tumors harboring KRAS G12C mutations and response to savolitinib in a tumor with MET exon 14 skipping mutation. Savolitinib also demonstrated in vivo radiation enhancement in our MET exon 14 mutated PDX. Early passage cell strains showed high consistency between patient and PDX tumors. Together, these data describe 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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1 University of Wisconsin, Department of Human Oncology, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607); University of Wisconsin, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607)
2 University of Wisconsin, Department of Human Oncology, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607)
3 Case Western Reserve University, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847)
4 University of Wisconsin, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607); University of Wisconsin, Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607)
5 University of Wisconsin, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607); University of Wisconsin, Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607); University of Wisconsin, Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607)
6 University of Wisconsin, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607); University of Wisconsin, Division of Hematology/Oncology, Department of Medicine, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607)
7 University of Wisconsin, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607); University of Wisconsin, Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607)
8 Cleveland Clinic, Department of Radiation Oncology, Taussig Cancer Institute, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725)
9 University of Wisconsin, Department of Human Oncology, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607); University of Wisconsin, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607); Madison, USA (GRID:grid.28803.31)