Abstract
Abstract Background: Although EGFR exon 20 insertion mutation is the third most common among EGFR-mutant NSCLC, this mutant clones are resistant to the first-generation EGFR TKIs. In addition, the efficacy of the second or third-generation EGFR TKIs is unknown in NSCLC with EGFR exon 20 insertion mutation. Methods: Various EGFR exon 20 insertion mutations were introduced into Ba/F3 cells as follows: A763_Y764insFQEA in C-helix; and V769_D770insASV, D770_N771insNPG, D770_N771insSVD, P772_H773insPR, H773_V774insNPH, H773_V774insH, and H773_V774insAH in loop following C-helix. The patient-derived SNU-3173 cell line was developed in a patient with EGFRH773_V774insAH mutation. Ba/F3 cells transfected with EGFR exon 20 insertion mutations and SNU-3173 were exposed to the EGFR TKIs (the 1st-generation gefitinib and erlotinib; the 2nd-generation dacomitinib and afatinib; and the 3rd-generation rociletinib, olmutinib, nazartinib, and osimertinib) and cell viability assays were performed. In addition, immunoblotting was performed to evaluate the downstream signals of EGFR pathway. Results: Cell viability assay showed that EGFR exon 20 insertion mutants are resistant to the 1st-generation EGFR TKIs, except for EGFRA763_Y764insFQEA-mutant Ba/F3 cells. IC50 values of the 2nd-generation EGFR TKIs are five to hundred-folds lower than the 1st-generation EGFR TKIs. The 2nd-generation EGFR TKIs were effective against EGFR exon 20 inserted Ba/F3 cells and down-regulated EGFR downstream signals. The 3rd-generation EGFR mutation-selective inhibitors showed a moderate efficacy except osimertinib that was effective and down-regulated EGFR downstream signals. In addition, SNU-3173 cells were moderately toxic to afatinib (IC50 46.2±5.2nM) as well as osimertinib (IC50 403.2±3.0nM). IC50 values of EGFR exon 20 insertion mutation Ba/F3 cellsIC50 (nM)FQEAASVSVDNPGPRHAHNPHGefitinib32.7525.7752.71597.01363.02581.02259.01701.0Erlotinib22.3486.9338.3765.7798.21523.01438.0562.1Dacomitinib0.00243.55.715.0205.0608.4556.312.3Afatinib0.0082.344.911.494.7297.7204.425.4Rociletinib219.7367.191.5131.21093.93710.05085.4498.7Olmutinib76.082.195.664.5332.6952.41406.6337.1Osimertinib3.68.18.9128.2247.2128.2880.338.2Nazartinib28.322.336.657.6747.8872.11606.8118.0 Conclusions: Overall, osimertinib showed effectiveness against NSCLC cells with EGFR exon 20 insertion mutations. Our results warrant a clinical trial of osimertinib in NSCLC patients with EGFR exon 20 insertion mutations. Citation Format: Yusoo Lee, Tae Min Kim, Dong-Wan Kim, Yong-Oon Ahn, Soyeon Kim, Bhumsuk Keam, Miso Kim, Dae Seog Heo. Osimertinib (AZD9291) is effective against NSCLC cells harboring EGFR exon 20 insertion mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3157. doi:10.1158/1538-7445.AM2017-3157
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