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Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy
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.
Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy
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.
Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy
Chen, Fan (author) / Liu, Jinpeng (author) / Flight, Robert M. (author) / Naughton, Kassandra J. (author) / Lukyanchuk, Alexsandr (author) / Edgin, Abigail R. (author) / Song, Xiulong (author) / Zhang, Haikuo (author) / Wong, Kwok‐Kin (author) / Moseley, Hunter N. B. (author)
Advanced Science ; 8
2021-11-01
11 pages
Article (Journal)
Electronic Resource
English
organoids , lung cancer , EGFR , bronchiolar , alveolar
Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer
| Wiley | 2022