EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as
Yoshihisa Kobayashi1, Yosuke Togashi2, Yasushi Yatabe3
1Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
Purpose:
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18.
Experimental Design:
Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined.
Results:
Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11-50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5-25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼ 80%) than to 1G TKIs (35%-56%) by compilation of data in the literature.
Conclusions:
Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations.
Insights
Lung cancers with exon 18 mutations are resistant to common EGFR tyrosine kinase inhibitors (TKIs). Afatinib and neratinib show promising efficacy against these rare mutations, offering new treatment avenues.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Common EGFR mutations in lung cancer respond to EGFR tyrosine kinase inhibitors (TKIs).
- EGFR exon 20 insertions (Ins20) confer resistance to existing TKIs.
- Limited data exists on the clinical significance and therapeutic response of EGFR exon 18 mutations.
Purpose of the Study:
- To investigate the oncogenic potential and TKI sensitivity of specific EGFR exon 18 mutations.
- To evaluate the efficacy of first-generation (1G), second-generation (2G), and third-generation (3G) TKIs against EGFR exon 18 mutations.
Main Methods:
- Retrospective review of lung cancer mutational status (2001-2015).
- Introduction of three representative exon 18 mutations (G719A, E709K, Del18) into Ba/F3 and NIH/3T3 cell lines.
- Determination of 90% inhibitory concentrations (IC90s) for various TKIs against engineered cell lines.
Main Results:
- Exon 18 mutations (G719X, E709X, Del18) were found in 3.2% of EGFR mutations analyzed.
- Engineered cells with exon 18 mutations demonstrated oncogenic potential.
- TKIs showed varied efficacy: 1G and 3G TKIs had high IC90s, while afatinib and neratinib demonstrated improved sensitivity against G719A and E709K mutations compared to Del19.
Conclusions:
- EGFR exon 18 mutations in lung cancer warrant clinical attention due to their distinct TKI resistance profiles.
- Afatinib and neratinib represent potential therapeutic options for lung cancers harboring exon 18 mutations.
- Current in vitro diagnostic kits may not detect all clinically relevant exon 18 mutations.
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