T790米
奥西默替尼
表皮生长因子受体抑制剂
突变体
癌症研究
突变
埃罗替尼
转染
酪氨酸激酶抑制剂
化学
酪氨酸激酶
表皮生长因子受体
分子生物学
药理学
医学
癌症
生物
吉非替尼
基因
受体
内科学
生物化学
作者
Kimihiro Ito,Makoto Nishio,Masanori Kato,Haruyasu Murakami,Yoshimi Aoyagi,Yuichiro Ohe,Takashige Okayama,Akihiro Hashimoto,Hirokazu Ohsawa,Gotaro Tanaka,Katsumasa Nonoshita,Satoru Ito,Keitaro Matsuo,Kazutaka Miyadera
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2019-05-01
卷期号:18 (5): 920-928
被引量:10
标识
DOI:10.1158/1535-7163.mct-18-0645
摘要
TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common EGFR mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T790M), and uncommon mutations (G719X and L861Q) with those of other EGFR-TKIs. We also commenced investigation of the clinical benefits of TAS-121. The IC50 for intracellular EGFR phosphorylation was determined by using Jump-In GripTite HEK293 cells transiently transfected with EGFR expression vectors. Mouse xenograft models were used to evaluate the antitumor activity of TAS-121. TAS-121 potently inhibited common activating and resistance EGFR mutations to the same extent as another third-generation EGFR-TKI (osimertinib). In addition, TAS-121 showed equivalent inhibitory activity against some uncommon mutations such as G719X and L861Q. Furthermore, TAS-121 demonstrated greater selectivity for mutant EGFRs versus the wild-type EGFR compared with other EGFR-TKIs. Moreover, TAS-121 displayed antitumor activity in SW48 (EGFR G719S) and NCI-H1975 (EGFR L858R/T790M) xenograft models, and achieved an objective response in patients with NSCLC with EGFR mutations including G719A mutation. In conclusion, TAS-121 is a novel third-generation EGFR-TKI and demonstrates antitumor activities in patients with NSCLC expressing either common or uncommon EGFR mutations.
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