Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases

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

doi:10.1038/s41598-021-81832-1

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.

Highlights

Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible
We demonstrate the utility of these patient-derived xenograft (PDX) by assessing their response to radiation and selumetinib in KRAS mutated xenografts and savolitinib in a MET exon 14 mutated xenograft
The lack of preclinical NSCLC brain metastasis models is one barrier that may be preventing the development of effective therapeutic strategies

Summary

Introduction

Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. 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 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. In a phase II study, patients with NSCLC and brain metastases with PD-L1 expression of at least 1%9 benefited from PD-1 blockade, with CNS responses (30%) similar to extracranial responses, indicating that immunotherapy can result in prolonged survival in a subset of patients These response rates are far below those seen following standard of care radiotherapy. Orthotopic intracranial implants allow cancer cells to more closely resemble their original patient tumors both phenotypically and genotypically given the influence of the brain m icroenvironment[11]

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Conclusion