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

Fan Chen1, Jinpeng Liu2, Robert M Flight3,4

  • 1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 8, 2021
PubMed

Insights

This study reveals that specific epidermal growth factor receptor (EGFR) mutations drive lung adenocarcinoma. Epigenetic differences in these EGFR-driven lung cancers influence drug vulnerabilities, aiding precision medicine strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Precision Medicine

Background:

  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are key treatments for lung adenocarcinoma.
  • Drug resistance to first- and second-generation EGFR TKIs necessitates novel therapeutic strategies, leading to the development of third-generation inhibitors like osimertinib.

Purpose of the Study:

  • To develop a model of EGFR-driven lung cancer with distinct epigenetic states.
  • To investigate the cellular origins and epigenetic plasticity of EGFR-mutated lung tumors.
  • To identify how epigenetic differences impact drug vulnerabilities in lung adenocarcinoma.

Main Methods:

  • Utilized 3D organotypic cultures to generate tumors with distinct epigenetic states.
  • Activated EGFR T790M/L858R mutations in lung epithelial cells to model lung cancer.
  • Passaged tumor clones orthotopically in mice to assess epigenetic stability and drug responses.

Main Results:

  • EGFR T790M/L858R mutations drive lung cancers with alveolar or bronchiolar features, originating from alveolar type 2 (AT2) cells or bronchioalveolar stem cells.
  • Tumor clones maintained distinct epigenetic profiles through serial passaging in mice.
  • These epigenetically distinct clones exhibited unique vulnerabilities to specific drugs.

Conclusions:

  • Epigenetic states are crucial in shaping the characteristics and drug responses of EGFR-driven lung cancers.
  • This research provides a framework for leveraging epigenetic information to stratify patients for targeted lung adenocarcinoma therapies.
  • Understanding epigenetic heterogeneity is vital for advancing precision medicine in lung cancer treatment.
Keywords:
EGFRalveolarbronchiolarlung cancerorganoids

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