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Updated: Mar 30, 2026
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed
Yuliana Yosaatmadja1, Shevan Silva2, James M Dickson1
1School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Abstract:
The discovery of genetic drivers of lung cancer in patient sub-groups has led to their use as predictive biomarkers and as targets for selective drug therapy. Some of the most important lung cancer drivers are mutations in the EGFR gene, for example, the exon 19 deletions and the L858R variant that confer sensitivity to the front line drugs erlotinib and gefitinib; the acquired T790M variants confer drug resistance and a poor prognosis. A challenge then in targeting EGFR is to produce drugs that inhibit both sensitising variants and resistance variants, leaving wild type protein in healthy cells unaffected. One such agent is AstraZeneca's "breakthrough" AZD9291 molecule that shows a 200-fold selectivity for T790M/L858R over wild type EGFR. Our X-ray crystal structure reveals the binding mode of AZD9291 to the kinase domain of wild type EGFR.
Insights
Targeting EGFR mutations in lung cancer is key. AZD9291 selectively inhibits sensitizing and resistance variants, offering a promising therapeutic strategy for EGFR-mutated lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Genetic drivers like EGFR mutations are crucial in lung cancer sub-groups.
- EGFR mutations (exon 19 deletions, L858R) predict sensitivity to erlotinib/gefitinib.
- Acquired T790M mutations confer resistance and poor prognosis.
Purpose of the Study:
- To investigate novel therapeutic strategies targeting both sensitizing and resistance EGFR mutations.
- To characterize the binding of AZD9291 to wild-type EGFR kinase domain.
Main Methods:
- X-ray crystallography was employed to determine the binding mode.
- Structural analysis of AZD9291 interaction with EGFR kinase domain.
Main Results:
- AZD9291 exhibits high selectivity (200-fold) for T790M/L858R variants over wild-type EGFR.
- The study reveals the precise binding mode of AZD9291 to wild-type EGFR kinase domain.
Conclusions:
- AZD9291 is a potent inhibitor targeting key EGFR mutations in lung cancer.
- Understanding the binding mechanism provides insights for developing next-generation EGFR inhibitors.
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