Related Experiment Video

Updated: Jun 16, 2026

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
09:38

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

Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor

D Ercan1, K Zejnullahu, K Yonesaka

  • 1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Oncogene
|February 2, 2010
PubMed

Insights

Resistance to irreversible EGFR inhibitors like PF00299804 in lung cancer can occur through EGFR T790M amplification. This highlights the need for new therapies targeting this common resistance mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like gefitinib and erlotinib treat mutant non-small cell lung cancers (NSCLCs).
  • Acquired resistance to these TKIs often involves a secondary EGFR T790M mutation.
  • Irreversible EGFR inhibitors, such as PF00299804, show promise against EGFR-mutant tumors with T790M.

Purpose of the Study:

  • To investigate resistance mechanisms to the irreversible EGFR inhibitor PF00299804.
  • To determine if EGFR T790M amplification contributes to resistance against irreversible EGFR TKIs.

Main Methods:

  • Generation of PF00299804-resistant cell line models harboring EGFR T790M.
  • Assessment of EGFR gene copy number and EGFR dependency in resistant cells.
  • In vitro and in vivo xenograft studies to model resistance development.

Main Results:

  • PF00299804-resistant models developed focal amplification of the EGFR gene, specifically involving the T790M-mutated allele.
  • Resistant cell lines remained dependent on EGFR signaling for viability.
  • Resistance was shown to arise from the selection of pre-existing EGFR T790M-amplified clones.

Conclusions:

  • EGFR T790M amplification is a significant resistance mechanism to irreversible EGFR TKIs, similar to reversible inhibitors.
  • This finding underscores the critical need for developing more potent therapies targeting EGFR T790M.
  • Results can inform clinical trial strategies for irreversible EGFR TKI therapies.

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