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Updated: Mar 19, 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

Published on: August 11, 2017

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Adaptive and Acquired Resistance to EGFR Inhibitors Converge on the MAPK Pathway

Pengfei Ma1, Yujie Fu2, Minjiang Chen3

  • 11. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;

Theranostics
|June 10, 2016
PubMed

Insights

Erlotinib resistance in lung cancer involves MAPK pathway reactivation. Targeting both EGFR and MAPK simultaneously may overcome adaptive and acquired resistance, offering a promising therapeutic strategy for EGFR mutant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Adaptive and acquired resistance to epidermal growth factor receptor (EGFR) kinase inhibitors like erlotinib significantly hinders treatment efficacy in lung cancer.
  • The precise mechanisms underlying both adaptive and acquired resistance to EGFR inhibitors remain incompletely understood.

Purpose of the Study:

  • To systematically model erlotinib resistance in lung cancer and elucidate the common or distinct mechanisms of adaptive and acquired resistance.
  • To investigate the potential of combined EGFR and MAPK pathway inhibition as a therapeutic strategy.

Main Methods:

  • Systematic modeling of erlotinib resistance in lung cancer models.
  • Analysis of MAPK signaling pathway activation and its dependence on MET receptor and CRAF/NRAS amplification.
  • Evaluation of combined EGFR and MAPK inhibition in preclinical models.

Main Results:

  • Feedback reactivation of the MAPK signaling pathway, dependent on the MET receptor, was identified as a key contributor to adaptive resistance.
  • Acquired resistance was also linked to MAPK pathway activation, driven by CRAF or NRAS amplification.
  • Combined inhibition of EGFR and MAPK effectively impeded the development of both adaptive and acquired resistance.

Conclusions:

  • Adaptive and acquired resistance to EGFR inhibitors can converge on the same MAPK pathway.
  • Cotargeting EGFR and MAPK represents a promising therapeutic approach for patients with EGFR mutant lung tumors.
Keywords:
EGFRMAPKepidermal growth factor receptor

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