Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors

Related Experiment Video

Updated: Feb 14, 2026

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
07:42

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

8.4K

D Westover1, J Zugazagoitia2,3,4,5, B C Cho6

  • 1Department of Medicine, Vanderbilt University Medical Center, Nashville, USA.

Annals of Oncology : Official Journal of the European Society for Medical Oncology
|February 21, 2018
PubMed

Insights

Identifying EGFR mutations is standard for non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs). However, resistance develops, necessitating research into mechanisms like the T790M mutation to improve treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Activating mutations in the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) predict response to EGFR tyrosine kinase inhibitors (TKIs).
  • Acquired therapeutic resistance to EGFR TKIs is a significant clinical challenge in NSCLC treatment.
  • Understanding resistance mechanisms is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To provide an overview of EGFR-mutant NSCLC treatment resistance.
  • To highlight molecular mechanisms underlying EGFR TKI resistance.
  • To discuss recent clinical trials and novel strategies to overcome resistance.

Main Methods:

  • Literature review of studies on EGFR-mutant NSCLC and TKI resistance.
  • Analysis of molecular mechanisms of acquired resistance, including specific mutations and genetic alterations.
  • Summary of clinical trial outcomes and emerging therapeutic approaches.

Main Results:

  • The T790M mutation is the most common mechanism (approx. 60%) of acquired resistance to first- and second-generation EGFR TKIs.
  • Other resistance mechanisms include MET amplification, ERBB2 amplification, and transformation to small-cell lung cancer.
  • Recent advances are expanding treatment options for patients with EGFR-mutant NSCLC.

Conclusions:

  • Acquired resistance to EGFR TKIs in NSCLC is a complex biological process.
  • Targeting resistance mechanisms, such as the T790M mutation, is key to improving patient outcomes.
  • Ongoing research and novel therapies are transforming the treatment landscape for EGFR-mutant NSCLC.

More Related Videos

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

18.7K
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

15.3K

Related Concept Videos

Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
19.0K
Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers01:26

Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers

Receptor tyrosine kinase inhibitors (TKIs) and calcium channel blockers (CCBs) are two critical categories of drugs employed in the treatment of pulmonary artery hypertension (PAH). PAH is a disease that causes high blood pressure in the pulmonary arteries, resulting in chest pain, fatigue, and shortness of breath.
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
561
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
15.2K
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

4.5K
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.1K
Resistivity01:22

Resistivity

When a voltage is applied to a conductor, an electrical field is generated, and charges in the conductor feel the force due to the electrical field. The current density that results depends on the electrical field and the properties of the material. In some materials, including metals at a given temperature, the current density is approximately proportional to the electrical field. In these cases, the current density can be modeled as:
4.6K