Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy

• Published in: Advanced science Vol. 8; no. 22; pp. e2101999 - n/a
• Main Authors: Chen, Fan, Liu, Jinpeng, Flight, Robert M., Naughton, Kassandra J., Lukyanchuk, Alexsandr, Edgin, Abigail R., Song, Xiulong, Zhang, Haikuo, Wong, Kwok‐Kin, Moseley, Hunter N. B., Wang, Chi, Brainson, Christine F.
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01-11-2021; John Wiley and Sons Inc; Wiley
• Subjects: Acrylamides - therapeutic use; alveolar; Aniline Compounds - therapeutic use; Animals; Antineoplastic Agents - therapeutic use; Biomarkers; bronchiolar; Cell cycle; Cell Line, Tumor; Disease Models, Animal; Drug resistance; EGFR; Epigenetics; ErbB Receptors - drug effects; Female; Gene expression; Growth factors; Humans; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Male; Males; Medical prognosis; Mice; Mice, Nude; Mutation; organoids; Precision medicine; Precision Medicine - methods; Protein Kinase Inhibitors - therapeutic use; Proteins; Pyrimidines - therapeutic use; Treatment Outcome; Tumors; lung cancer; bronchiolar; alveolar; organoids; EGFR
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202101999

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.
In the report, murine lung organoids derived from distinct lung epithelial cells are utilized for transformation via oncogenic epidermal growth factor receptor (EGFR). The findings show that EGFR has differential oncogenic capacity in distinct lung cells and that lung cell lineage identity influences response to therapies.