Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy
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, incl...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-11-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202101999 |
| _version_ | 1818928424817786880 |
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| author | Fan Chen Jinpeng Liu Robert M. Flight Kassandra J. Naughton Alexsandr Lukyanchuk Abigail R. Edgin Xiulong Song Haikuo Zhang Kwok‐Kin Wong Hunter N. B. Moseley Chi Wang Christine F. Brainson |
| author_facet | Fan Chen Jinpeng Liu Robert M. Flight Kassandra J. Naughton Alexsandr Lukyanchuk Abigail R. Edgin Xiulong Song Haikuo Zhang Kwok‐Kin Wong Hunter N. B. Moseley Chi Wang Christine F. Brainson |
| author_sort | Fan Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T03:28:42Z |
| format | Article |
| id | doaj.art-1d70799b294842b6a8cf3f7bd6a3471b |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-20T03:28:42Z |
| publishDate | 2021-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-1d70799b294842b6a8cf3f7bd6a3471b2022-12-21T19:55:02ZengWileyAdvanced Science2198-38442021-11-01822n/an/a10.1002/advs.202101999Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to TherapyFan Chen0Jinpeng Liu1Robert M. Flight2Kassandra J. Naughton3Alexsandr Lukyanchuk4Abigail R. Edgin5Xiulong Song6Haikuo Zhang7Kwok‐Kin Wong8Hunter N. B. Moseley9Chi Wang10Christine F. Brainson11Department of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Internal Medicine University of Kentucky Lexington KY 40536 USADepartment of Molecular and Cellular Biochemistry University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADNAtrix 10355 Science Center Drive, Suite 110 San Diego CA 92121 USALaura and Isaac Perlmutter Cancer Center NYU Langone Medical Center New York University New York NY 10016 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Internal Medicine University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USAAbstract 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.https://doi.org/10.1002/advs.202101999alveolarbronchiolarEGFRlung cancerorganoids |
| spellingShingle | Fan Chen Jinpeng Liu Robert M. Flight Kassandra J. Naughton Alexsandr Lukyanchuk Abigail R. Edgin Xiulong Song Haikuo Zhang Kwok‐Kin Wong Hunter N. B. Moseley Chi Wang Christine F. Brainson Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy Advanced Science alveolar bronchiolar EGFR lung cancer organoids |
| title | Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy |
| title_full | Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy |
| title_fullStr | Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy |
| title_full_unstemmed | Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy |
| title_short | Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy |
| title_sort | cellular origins of egfr driven lung cancer cells determine sensitivity to therapy |
| topic | alveolar bronchiolar EGFR lung cancer organoids |
| url | https://doi.org/10.1002/advs.202101999 |
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