Uncovering the Molecular Basis for the Better Gefitinib Sensitivity of EGFR with Complex Mutations over Single Rare Mutation: Insights from Molecular Simulations

Abstract

Epidermal growth factor receptor (EGFR) is an intensively focused target for anti-tumor compounds used in non-small cell lung cancer (NSCLC) therapy. Compared to the classical activating mutations, there are still many uncommon EGFR mutations associated with poorer responses to EGFR inhibitors. A detailed understanding of the molecular basis for multiple EGFR mutants exhibiting diverse responses to inhibitors is of critical importance for related drug development. Herein, we explored the molecular determinants contributing to the distinct responses of EGFR with a single rare mutation (G719S) or combined mutations (G719S/L858R and G719S/l861Q) to Gefitinib (IRE). Our results indicated that interactions, formed within the tetrad of residues S768 (in the αC-helix), D770 (in the αC-β4 loop), Y827 (in the αE-helix), and R831 (in the catalytic loop), play an important role in the stability of αC-helix and the maintenance of K745–E762 salt bridge in the absence of IRE, which are weakened in the EGFRG719S system and enhanced in the EGFRG719S/L858R system upon IRE binding. Besides, the introduced hydrogen bonds by the co-occurring mutation partner also contribute to the stability of αC-helix. The work done for inhibitor dissociation suggests that IRE exhibits a stronger binding affinity to EGFRG719S/L858R mutant. Together, these findings provide a deeper understanding of minor mutations, which is essential for drug development targeting EGFR with less common mutations.

Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations

“…5a ). Helix αC changes that result from profile 2 exon 19 deletions between β3 and αC are presumably communicated to αE through these interactions, which interestingly were also recently implicated in differential gefitinib sensitivity in molecular dynamics studies 46 . The altered αE peptide also includes M825, the side chain of which contacts H835 in the conserved HRD motif at the beginning of the TKD’s catalytic loop—propagating αC changes to the catalytic loop.…”

Successful treatment of lung adenocarcinoma complicated with a rare compound EGFR mutation L833V/H835L using aumolertinib: a case report and literature review

“…In the early stage, gefitinib was frequently administered to treat patients with L833V/H835L mutations, this preference may be attributed to previous findings that gefitinib exhibit activity in patients with compound EGFR-mutations (the response rate was 50%), albeit with lower efficacy compared to patients with common mutations ( Yu et al, 2018 ). Li et al also proved a more favorable response to gefitinib in patients with compound EGFR mutations compared to those with a single rare variant through molecular dynamics simulations assay ( Li et al, 2022 ). Among the 9 cases included in Table 1 , 4 patients were treated with the gefitinib.…”

A L833V/H835L EGFR variant lung adenocarcinoma with skin metastasis: A case report and literature review

“…used molecular dynamics simulations to thoroughly investigate the molecular basis of gefitinib sensitivity of EGFR compound variants and single rare variants. The results showed that EGFR compound variants were more sensitive to gefitinib than single rare variants [ 6 ]. In terms of clinical treatment data, some studies found that patients with compound variants had an ORR of 6.2%–16.7% in first-line EGFR-TKI therapy, much lower than patients with single or classical EGFR variants (62.1%–84.6%), leading to varying degrees of shortened PFS and overall survival (OS) [ 7 , 8 ].…”