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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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GRHL2-HER3 and E-cadherin mediate EGFR-bypass drug resistance in lung cancer cells

Fumiya Ito1, Wakiko Iwata1, Yoshihiro Adachi1

  • 1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Frontiers in Cell and Developmental Biology
|February 3, 2025
PubMed

Insights

Drug resistance in lung cancer is a major challenge. This study reveals that the transcription factor GRHL2 and increased E-cadherin drive resistance to EGFR inhibitors like erlotinib, suggesting new combination therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance Mechanisms

Background:

  • Epidermal growth factor receptor (EGFR) is a key target in cancer therapy, particularly for lung cancer.
  • Resistance to EGFR inhibitors, such as erlotinib, is a significant clinical challenge, limiting treatment efficacy.
  • Understanding the molecular mechanisms underlying acquired resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to erlotinib in lung cancer cells.
  • To identify novel molecular targets for overcoming erlotinib resistance.
  • To explore the role of GRHL2, HER3, and E-cadherin in erlotinib resistance.

Main Methods:

  • Establishment of an erlotinib-resistant (ER) lung cancer cell line (A549) through prolonged drug exposure.
  • RNA sequencing to identify differentially expressed genes in ER cells.
  • Gene knockdown and knockout experiments to assess the functional role of identified genes (GRHL2, HER3, E-cadherin).
  • Cell-cell adhesion assays and IC50 measurements to quantify drug resistance.

Main Results:

  • ER cells exhibited increased erlotinib resistance, decreased EGFR levels, and enhanced tumor growth.
  • Upregulation of transcription factor GRHL2 was identified as a critical driver of erlotinib resistance.
  • GRHL2 promotes resistance by upregulating the receptor tyrosine kinase HER3.
  • Increased cell-cell adhesion, mediated by upregulated E-cadherin, also contributes to erlotinib resistance, largely independent of GRHL2.

Conclusions:

  • Acquired erlotinib resistance in lung cancer involves multiple parallel pathways, including GRHL2-HER3 signaling and E-cadherin-mediated cell-cell adhesion.
  • Targeting both GRHL2-HER3 and E-cadherin pathways may be necessary to overcome erlotinib resistance.
  • These findings offer novel insights into drug resistance mechanisms and suggest potential combination therapies for lung cancer treatment.
Keywords:
EGFRGRHL2HER3cadherindrug resistancelung cancer

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