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ORIGINAL RESEARCH article

Front. Cell Dev. Biol.
Sec. Cell Adhesion and Migration
Volume 12 - 2024 | doi: 10.3389/fcell.2024.1511190

GRHL2-HER3 and E-cadherin Mediate EGFR-bypass Drug Resistance in Lung Cancer Cells

Provisionally accepted
Miho Iijima Miho Iijima 1,2*Fumiya Ito Fumiya Ito 2Wakiko Iwata Wakiko Iwata 2Hiromi Sesaki Hiromi Sesaki 2
  • 1 School of Medicine, Johns Hopkins University, Baltimore, United States
  • 2 Johns Hopkins Medicine, Johns Hopkins University, Baltimore, Maryland, United States

The final, formatted version of the article will be published soon.

    Epidermal growth factor receptor (EGFR) is a major oncogenic protein, and thus EGFR-targeting therapies are widely used in patients with various types of cancer, including lung cancer. However, resistance to EGFR inhibitors, such as erlotinib, presents a significant challenge in treating lung cancer. In this study, we established an EGFR-independent, erlotinib-resistant (ER) phenotype in lung cancer A549 cells by exposing them to erlotinib for an extended period. The resulting ER cells exhibited a dramatic increase in erlotinib resistance, a decreased EGFR protein level, and enhanced tumor growth, suggesting a robust mechanism bypassing EGFR inhibition. RNA sequencing identified the transcription factor GRHL2 as a critical player in this resistance. GRHL2 was upregulated in ER cells, and its knockdown and knockout significantly reduced erlotinib resistance. Further analysis revealed that GRHL2 upregulates the receptor tyrosine kinase HER3, and that HER3 knockdown similarly decreases the IC50 for erlotinib. Additionally, ER cells showed increased cellcell adhesion, linked to upregulated E-cadherin. E-cadherin was found to be vital for erlotinib resistance, largely independent of GRHL2, highlighting multiple parallel pathways sustaining resistance. These findings provide a novel mechanism of drug resistance and suggest that combination therapies targeting both GRHL2-HER3 and E-cadherin-mediated pathways may be necessary to overcome erlotinib resistance in lung cancer.

    Keywords: EGFR, lung cancer, Drug Resistance, GRHL2, HER3, cadherin

    Received: 14 Oct 2024; Accepted: 20 Dec 2024.

    Copyright: © 2024 Iijima, Ito, Iwata and Sesaki. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Miho Iijima, School of Medicine, Johns Hopkins University, Baltimore, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.