Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR-Mutated Non–Small Cell Lung Cancer
| Autor: | Shigenari Nukaga, Hiroyuki Yasuda, Tomoko Betsuyaku, Keita Masuzawa, Tatsuya Niimi, Hideki Sakagami, Junko Hamamoto, Katsuhiko Naoki, Toshiyuki Hirano, Ichiro Kawada, Kenzo Soejima, Shinya Mimasu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Mutation biology Cell growth Chemistry Cancer medicine.disease medicine.disease_cause respiratory tract diseases 03 medical and health sciences Exon T790M 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis medicine Cancer research biology.protein Osimertinib Epidermal growth factor receptor Tyrosine kinase |
| Zdroj: | Molecular Cancer Therapeutics. 17:740-750 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-17-1033 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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