Related Experiment Video

Updated: Jul 16, 2025

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

8.9K

Coevolution-based computational approach to detect resistance mechanism of epidermal growth factor receptor

Gyan Prakash Rai1, Asheesh Shanker1

  • 1Department of Bioinformatics, Central University of South Bihar, Gaya, Bihar 824236, India.

Biochimica Et Biophysica Acta. Molecular Cell Research
|September 20, 2023
PubMed

Insights

Compensatory mutations in epidermal growth factor receptor (EGFR) drive resistance to non-small cell lung cancer treatments. These EGFR mutations alter drug-binding pockets, impacting tyrosine kinase inhibitor efficacy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal growth factor receptor (EGFR) is crucial in non-small cell lung cancer (NSCLC) progression, driving metastasis, angiogenesis, and inhibiting apoptosis.
  • Tyrosine kinase inhibitors (TKIs) targeting EGFR show efficacy but are limited by acquired drug resistance, often within a year of treatment.
  • Acquired resistance to EGFR-TKIs in NSCLC is frequently mediated by secondary mutations within the EGFR gene.

Purpose of the Study:

  • To investigate the evolutionary mechanisms behind drug resistance in EGFR.
  • To identify compensatory mutations in EGFR that contribute to TKI resistance.
  • To understand how these mutations affect the drug-binding pocket and ligand interaction.

Main Methods:

  • Analysis of EGFR mutations in resistant NSCLC cases.
  • Structural analysis of EGFR protein with compensatory mutations.
  • In silico modeling of drug-ligand interactions (gefitinib, erlotinib) with mutated EGFR.

Main Results:

  • Compensatory mutations were detected in EGFR, suggesting an evolutionary adaptation to drug pressure.
  • These mutations were found to enlarge the drug-binding pocket of EGFR.
  • The enlarged pocket alters the binding orientation of TKIs like gefitinib and erlotinib, leading to reduced efficacy and drug resistance.

Conclusions:

  • Coevolutionary forces significantly influence EGFR structure, promoting resistance to targeted therapies.
  • Understanding evolution-induced structural changes in EGFR is key to overcoming drug resistance.
  • This research provides insights for designing next-generation TKIs with improved efficacy against resistant NSCLC.
Keywords:
CoevolutionDrug resistanceEGFRErlotinibGefitinibLung cancerMutations

More Related Videos

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

10.6K
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

8.7K

Related Concept Videos

Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.5K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.3K
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
2.5K
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
5.8K