L858R/L718Q and L858R/L792H Mutations of EGFR Inducing Resistance Against Osimertinib by Forming Additional Hydrogen
Ibrahim A Imam1, Shatha Al Adawi1, Xiaoqi Liu2,3
1Department of Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky, USA.
Abstract:
Acquired resistance to first-line treatments in various cancers both promotes cancer recurrence as well as limits effective treatment. This is true for epidermal growth factor receptor (EGFR) mutations, for which secondary EGFR mutations are one of the principal mechanisms conferring resistance to the covalent inhibitor osimertinib. Thus, it is very important to develop a deeper understanding of the secondary mutational resistance mechanisms associated with EGFR mutations arising in tumors treated with osimertinib to expedite the development of innovative therapeutic drugs to overcome acquired resistance. This work uses all-atom molecular dynamics (MD) simulations to investigate the conformational variation of two reported EGFR mutants (L858R/L718Q and L858R/L792H) that resist osimertinib. The wild-type EGFR kinase domain and the L858R mutant are used as the reference. Our MD simulation results revealed that both the L718Q and L792H secondary mutations induce additional hydrogen bonds between the residues in the active pocket and the residues with the water molecules. These additional hydrogen bonds reduce the exposure area of C797, the covalent binding target of osimertinib. The additional hydrogen bonds also influence the binding affinity of the EGFR kinase domain by altering the secondary structure and flexibility of the amino acid residues in the domain. Our work highlights how the two reported mutations may alter both residue-residue and residue-solvent hydrogen bonds, affecting protein binding properties, which could be helpful for future drug discovery.
Insights
Secondary mutations in epidermal growth factor receptor (EGFR) confer resistance to osimertinib. Molecular dynamics simulations reveal these mutations alter hydrogen bonds, reducing drug binding and aiding resistance to EGFR inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- Acquired resistance to cancer therapies, particularly EGFR inhibitors like osimertinib, limits treatment efficacy.
- Secondary mutations in the epidermal growth factor receptor (EGFR) are a primary cause of resistance to osimertinib.
- Understanding these resistance mechanisms is crucial for developing next-generation therapies.
Purpose of the Study:
- To investigate the molecular mechanisms by which specific secondary mutations in EGFR confer resistance to osimertinib.
- To explore the conformational changes and altered binding properties of EGFR mutants using computational simulations.
Main Methods:
- All-atom molecular dynamics (MD) simulations were employed.
- Simulations were performed on wild-type EGFR kinase domain, L858R mutant, and two secondary mutants (L858R/L718Q and L858R/L792H).
- Analysis focused on conformational variations, hydrogen bonding patterns, and binding affinity.
Main Results:
- The L718Q and L792H secondary mutations introduce additional hydrogen bonds within the active pocket and with water molecules.
- These alterations reduce the accessibility of C797, the binding site for osimertinib.
- Changes in hydrogen bonding affect the secondary structure and flexibility of the EGFR kinase domain, impacting binding affinity.
Conclusions:
- The studied secondary EGFR mutations (L718Q, L792H) confer osimertinib resistance by modifying intra- and inter-molecular hydrogen bonding networks.
- These modifications alter protein binding properties and drug target accessibility.
- Findings provide insights for designing novel EGFR inhibitors to overcome acquired resistance.
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