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Integrating clinical outcomes with molecular simulations to guide the selection of non‑classical EGFR‑TKIs: A comprehensive analysis and development of treatment strategies

  • Authors:
    • Fang Wei
    • Niu Niu
    • Chang Li
    • Ge Gao
    • Nan Li
    • Yan Wang
  • View Affiliations / Copyright

    Affiliations: Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong 518116, P.R. China, School of Computer and Information, Hefei University of Technology, Hefei, Anhui 230009, P.R. China, School of Computer and Information, Hefei University of Technology, Hefei, Anhui 230009, P.R. China, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
    Copyright: © Wei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 277
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    Published online on: August 14, 2026
       https://doi.org/10.3892/etm.2026.13272
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Abstract

Non‑classical EGFR mutations in non‑small cell lung cancer (NSCLC) are uncommon and heterogeneous, and the optimal EGFR‑tyrosine kinase inhibitor (TKI) strategy remains uncertain. This retrospective study analyzed 31 patients with advanced/metastatic, recurrent or post‑resection NSCLC harboring non‑classical EGFR mutations who were treated at the Chinese Academy of Medical Sciences Cancer Hospital (Beijing, China) between 2013 and 2020, with follow‑up updated to June 30, 2024. EGFR mutation status was obtained from routine clinical molecular pathology reports based on clinically validated targeted next‑generation sequencing and/or amplification refractory mutation system PCR. Molecular docking and Prime Molecular Mechanics Generalized Born Surface Area (MM‑GBSA) calculations were used to evaluate drug‑mutant EGFR binding. Clinical outcomes varied by mutation subtype and EGFR‑TKI regimen; relatively favorable progression‑free survival (PFS) was observed with dacomitinib in L861Q and with afatinib‑ or dacomitinib‑based treatment in selected S768I compound mutations. Exploratory Spearman analysis suggested that lower docking scores and more negative MM‑GBSA ∆G_bind values were associated with longer PFS. These findings provide hypothesis‑generating evidence that molecular simulation may help inform personalized EGFR‑TKI selection for non‑classical EGFR mutations, although validation in larger, consecutive and prospective multicenter cohorts is required.
View Figures

Figure 1

Proportion of PD types by different
mutations. PD, progressive disease; CP, clinical progression; LP,
local progression; SP, slow progression.

Figure 2

Structural superimposition of the
WT-EGFR protein and six non-classical mutant EGFR proteins. (A)
Three-dimensional structure of the wild-type EGFR protein; (B)
Superimposed structures of the WT-EGFR protein and six
non-classical mutant EGFR proteins. WT, wild-type.

Figure 3

Two-dimensional binding interactions
of EGFR-tyrosine kinase inhibitors with WT-EGFR and single-point
mutants G719A and L861Q. WT, wild-type.

Figure 4

Two-dimensional binding interactions
of EGFR- tyrosine kinase inhibitors with the compound EGFR mutants
G719A+S768I, G719C+S768I, G719S+S768I and V769L+S768I.
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Copy and paste a formatted citation
Spandidos Publications style
Wei F, Niu N, Li C, Gao G, Li N and Wang Y: Integrating clinical outcomes with molecular simulations to guide the selection of non‑classical EGFR‑TKIs: A comprehensive analysis and development of treatment strategies. Exp Ther Med 32: 277, 2026.
APA
Wei, F., Niu, N., Li, C., Gao, G., Li, N., & Wang, Y. (2026). Integrating clinical outcomes with molecular simulations to guide the selection of non‑classical EGFR‑TKIs: A comprehensive analysis and development of treatment strategies. Experimental and Therapeutic Medicine, 32, 277. https://doi.org/10.3892/etm.2026.13272
MLA
Wei, F., Niu, N., Li, C., Gao, G., Li, N., Wang, Y."Integrating clinical outcomes with molecular simulations to guide the selection of non‑classical EGFR‑TKIs: A comprehensive analysis and development of treatment strategies". Experimental and Therapeutic Medicine 32.4 (2026): 277.
Chicago
Wei, F., Niu, N., Li, C., Gao, G., Li, N., Wang, Y."Integrating clinical outcomes with molecular simulations to guide the selection of non‑classical EGFR‑TKIs: A comprehensive analysis and development of treatment strategies". Experimental and Therapeutic Medicine 32, no. 4 (2026): 277. https://doi.org/10.3892/etm.2026.13272
Copy and paste a formatted citation
x
Spandidos Publications style
Wei F, Niu N, Li C, Gao G, Li N and Wang Y: Integrating clinical outcomes with molecular simulations to guide the selection of non‑classical EGFR‑TKIs: A comprehensive analysis and development of treatment strategies. Exp Ther Med 32: 277, 2026.
APA
Wei, F., Niu, N., Li, C., Gao, G., Li, N., & Wang, Y. (2026). Integrating clinical outcomes with molecular simulations to guide the selection of non‑classical EGFR‑TKIs: A comprehensive analysis and development of treatment strategies. Experimental and Therapeutic Medicine, 32, 277. https://doi.org/10.3892/etm.2026.13272
MLA
Wei, F., Niu, N., Li, C., Gao, G., Li, N., Wang, Y."Integrating clinical outcomes with molecular simulations to guide the selection of non‑classical EGFR‑TKIs: A comprehensive analysis and development of treatment strategies". Experimental and Therapeutic Medicine 32.4 (2026): 277.
Chicago
Wei, F., Niu, N., Li, C., Gao, G., Li, N., Wang, Y."Integrating clinical outcomes with molecular simulations to guide the selection of non‑classical EGFR‑TKIs: A comprehensive analysis and development of treatment strategies". Experimental and Therapeutic Medicine 32, no. 4 (2026): 277. https://doi.org/10.3892/etm.2026.13272
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