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Mol Cancer Ther. 2018 Apr;17(4):740-750. doi: 10.1158/1535-7163.MCT-17-1033. Epub 2018 Feb 21.

Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR-Mutated Non-Small Cell Lung Cancer.

Author information

1
Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
2
Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan. hiroyukiyasuda@a8.keio.jp.
3
Kitasato University School of Medicine, Department of Respiratory Medicine, Kanagawa, Japan.
4
Medicinal Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan.
5
Research Program Management Office, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan.

Abstract

Multiple epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) have been developed to effectively inhibit EGFR-derived signals in non-small cell lung cancer (NSCLC). In this study, we assessed the efficacy of EGFR-TKIs, including a novel third-generation inhibitor naquotinib (ASP8273), in clinically relevant EGFR mutations, including L858R, exon 19 deletion, L858R+T790M, exon 19 deletion+T790M with or without a C797S mutation, and several exon 20 insertion mutations. Using structural analyses, we also elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in EGFR exon 20 insertion mutations. The efficacy of naquotinib in cells with L858R, exon 19 deletion and exon 19 deletion+T790M was comparable with that of osimertinib. Interestingly, naquotinib was more potent than osimertinib for L858R+T790M. Additionally, naquotinib and osimertinib had comparable efficacy and a wide therapeutic window for cells with EGFR exon 20 insertions. Structural modeling partly elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in two EGFR exon 20 insertion mutants, A767_V769dupASV and Y764_V765insHH. In summary, we have characterized the efficacy of EGFR-TKIs for NSCLC using in vitro and structural analyses and suggested the mechanism of activation and resistance to EGFR-TKIs of EGFR exon 20 insertion mutations. Our findings should guide the selection of appropriate EGFR-TKIs for the treatment of NSCLC with EGFR mutations and help clarify the biology of EGFR exon 20 insertion mutations. Mol Cancer Ther; 17(4); 740-50. ©2018 AACR.

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