Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells or bronchioalveolar stem cells, but not basal cells or club cells of the trachea. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions.

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Published in Advanced Science, v. 8, issue 22, 2101999.

© 2021 The Authors

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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This work was supported in part by NCI K22 CA201036, Kentucky Lung Cancer Research Program, V Foundation Scholar Award, American Cancer Society Institutional Research Grant IRG-85-001-25 and NCI R01 CA237643, American Cancer Society Research Scholar Grant 133123-RSG-19-081-01-TBG and American Association for Cancer Research Innovation and Discovery Grant (C.F.B.), and NIGMS P20 GM121327-03 (C.F.B. and H.N.B.M.). This research was also supported by the Biostatistics and Bioinformatics Shared Resource Facility, Oncogenomics Shared Resource Facility, Biospecimen Procurement and Translational Pathology Shared Resource Facility and Flow Cytometry and Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558).

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The RNA-sequencing data for study are available at the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database under GSE180360. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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