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

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

doi:10.1002/advs.202101999

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

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

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English
Article number	2101999
Journal	Advanced Science
Volume	8
Issue number	22
DOIs	https://doi.org/10.1002/advs.202101999
State	Published - Nov 17 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH

Funding

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).

Funders	Funder number
The Markey Biostatistics and Bioinformatics Shared Resource Facility
Kentucky Lung Cancer Research Program
American Association for Cancer Research
American Cancer Society	IRG‐85‐001‐25, R01 CA237643, 133123‐RSG‐19‐081‐01‐TBG
National Childhood Cancer Registry – National Cancer Institute	P30CA177558, K22 CA201036
National Institute of General Medical Sciences	P20GM121327
University of Kentucky Markey Cancer Center

Keywords

EGFR
alveolar
bronchiolar
lung cancer
organoids

ASJC Scopus subject areas

Medicine (miscellaneous)
General Chemical Engineering
General Materials Science
Biochemistry, Genetics and Molecular Biology (miscellaneous)
General Engineering
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/advs.202101999

Cite this

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title = "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, 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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doi = "10.1002/advs.202101999",

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AU - Song, Xiulong

AU - Zhang, Haikuo

AU - Wong, Kwok Kin

AU - Moseley, Hunter N.B.

AU - Wang, Chi

AU - Brainson, Christine F.

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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