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 journalArticlepeer-review

11 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 languageEnglish
Article number2101999
JournalAdvanced Science
Volume8
Issue number22
DOIs
StatePublished - Nov 17 2021

Bibliographical note

Funding Information:
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).

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

Keywords

  • EGFR
  • alveolar
  • bronchiolar
  • lung cancer
  • organoids

ASJC Scopus subject areas

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

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