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Updated: May 8, 2026

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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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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EGFR-19del nuclear translocation increases HDAC7 expression inhibiting the Hippo pathway and exacerbating TKI

Yuheng Feng1, Minghao Wang2, Yang Liu1

  • 1Department of Pathology, First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China.

Theranostics
|May 7, 2026
PubMed
Abstract

Insights

Nuclear EGFR-19del promotes TKI resistance in lung adenocarcinoma by elevating HDAC7, which inhibits the Hippo pathway. This finding suggests combined TKI and HDAC inhibitor therapy for EGFR-19del LUAD.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance Mechanisms

Background:

  • Epidermal growth factor receptor (EGFR) mutations, specifically EGFR-19del, are common in lung adenocarcinoma (LUAD).
  • Acquired resistance to tyrosine kinase inhibitors (TKIs) is a major clinical challenge in EGFR-mutated LUAD.
  • EGFR membrane-cytoplasmic-nuclear translocation is observed in TKI-resistant LUAD, but its precise role remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which nuclear EGFR-19del confers resistance to TKIs in LUAD.
  • To investigate the role of histone deacetylase 7 (HDAC7) in TKI resistance and the Hippo pathway.

Main Methods:

  • RNA sequencing and immunohistochemistry to assess HDAC7 expression in TKI-resistant LUAD.
  • In vitro and in vivo functional assays to evaluate the impact of HDAC7 on LUAD malignancy and TKI sensitivity.
  • Mass spectrometry, dual-luciferase, chromatin immunoprecipitation, and coimmunoprecipitation assays to explore molecular interactions and pathway regulation.

Main Results:

  • Nuclear EGFR-19del translocation correlated with increased HDAC7 expression in TKI-resistant LUAD cells.
  • HDAC7 overexpression enhanced LUAD malignancy and reduced TKI sensitivity, while its knockdown or TSA treatment suppressed tumor growth and improved TKI sensitivity.
  • HDAC7 deacetylates LATS1, inhibiting the Hippo pathway, and nuclear EGFR-19del acts as a coactivator for HDAC7 transcription via STAT3.

Conclusions:

  • Nuclear EGFR-19del inhibits the Hippo pathway through HDAC7-mediated LATS1 deacetylation.
  • This mechanism contributes to TKI resistance in EGFR-19del LUAD.
  • Targeting both TKIs and HDAC inhibitors presents a potential therapeutic strategy to overcome drug resistance in this patient population.
Keywords:
EGFRHDAC7Hippo pathwayLATS1YAPdrug resistance

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