Abstract
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.
Highlights
Commons, and the Medical Toxicology Commons Right click to open a feedback form in a new tab to let us know how this document benefits you
We discovered that epidermal growth factor receptor (EGFR) mutation led to lung cancer with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells or bronchioalveolar stem cells (BASCs), but not basal cells or club cells of the trachea
The tumors that formed by intranasal adeno-Cre installation were almost exclusively alveolar type adenocarcinoma, with rare tumor types exhibiting bronchiolar features according to their immunofluorescence (IF) staining, it is difficult to distinguish them by their histological morphologies (Figure 1C,D)
Summary
The Medical Toxicology Commons Right click to open a feedback form in a new tab to let us know how this document benefits you. Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase in the proximal airways as well as bronchioalveolar stem cells (BASCs) and inhibitors (TKIs) is one of the major precision medicine treatment options for alveolar type 2 (AT2) cells in the distal lung adenocarcinoma. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states airways.[1,2,3] Lung adenocarcinoma has been postulated to originate from club cells, AT2 cells, or BASCs, while squamous cell carcinomas likely arise from basal cells.[4,5,6] Experimental models have shown through 3D organotypic cultures are described here. Epigenetic biomarkers, including markers of Understanding the cellular and molecular origins of lung cancer cell states, could add crucial additional predictions of drug rewill help us to define ways to prevent this deadly disease.
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