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Oncotarget. 2017 Nov 6;8(62):105479-105491. doi: 10.18632/oncotarget.22297. eCollection 2017 Dec 1.

Characterization of the efficacies of osimertinib and nazartinib against cells expressing clinically relevant epidermal growth factor receptor mutations.

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Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
Keio Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.


Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) were developed to overcome EGFR T790M-mediated resistance to first- and second-generation EGFR-TKIs. Third-generation EGFR-TKIs, such as osimertinib and nazartinib, are effective for patients with the EGFR T790M mutation. However, there are no direct comparison data to guide the selection of a third-generation EGFR-TKI for patients with different EGFR mutations. We previously established an in vitro model to estimate the therapeutic windows of EGFR-TKIs by comparing their relative efficacies against cells expressing mutant or wild type EGFRs. The present study used this approach to characterize the efficacy of third-generation EGFR-TKIs and compare them with that of other EGFR-TKIs. Treatment efficacy was examined using human lung cancer-derived cell lines and Ba/F3 cells, which were transduced with clinically relevant mutant EGFRs. Interestingly, mutation-related differences in EGFR-TKI sensitivity were observed. For classic EGFR mutations (exon 19 deletion and L858R, with or without T790M), osimertinib showed lower IC50 values and wider therapeutic windows than nazartinib. For less common EGFR mutations (G719S or L861Q), afatinib showed the lowest IC50 values. For G719S+T790M or L861Q+T790M, the IC50 values of osimertinib and nazartinib were around 100 nM, which was 10- to 100-fold higher than those for classic+T790M mutations. On the contrary, osimertinib and nazartinib showed similar efficacies in cells expressing EGFR exon 20 insertions. The findings highlight the diverse mutation-related sensitivity pattern of EGFR-TKIs. These data may help in the selection of EGFR-TKIs for non-small cell lung cancer patients harboring EGFR mutations.


EGFR mutations; EGFR tyrosine kinase inhibitors; lung cancer; nazartinib; osimertinib

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