Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions

奥西默替尼 癌症研究 外显子 酪氨酸激酶 表皮生长因子受体 酪氨酸激酶抑制剂 激酶 埃罗替尼 化学 突变体 癌症 吉非替尼 生物 遗传学 信号转导 基因
作者
Nicolas Floc’h,Matthew J. Martin,Jonathan W. Riess,Jonathan P. Orme,Anna D. Staniszewska,Ludovic Ménard,Maria Emanuela Cuomo,Daniel O’Neill,Richard A. Ward,M. Raymond V. Finlay,Darren McKerrecher,Mingshan Cheng,Daniel P. Vang,Rebekah A. Burich,James Keck,David R. Gandara,Philip C. Mack,Darren A.E. Cross
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:17 (5): 885-896 被引量:99
标识
DOI:10.1158/1535-7163.mct-17-0758
摘要

Abstract EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non–small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC. Mol Cancer Ther; 17(5); 885–96. ©2018 AACR.
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