EGFR T790M and C797S Mutations as Mechanisms of Acquired Resistance to Dacomitinib
EGFR T790M and C797S Mutations as Mechanisms of Acquired Resistance to Dacomitinib
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DOI：
10.1016/j.jtho.2018.01.009
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发表时间：
2018-05-01
影响因子：
20.4
通讯作者：
Mitsudomi, Tetsuya
中科院分区：
文献类型：
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作者：
Kobayashi, Yoshihisa;Fujino, Toshio;Mitsudomi, Tetsuya
在最近的ARCHER 1050试验中，就egfr突变型肺癌患者的无进展生存期而言，达科米替尼优于吉非替尼。然而，尽管最初有明显的反应，肺癌最终获得对这些抑制剂的耐药性。本研究旨在阐明体外对达克替尼获得性耐药的机制。方法：采用n -乙基-n -亚硝基脲（ENU）诱变法暴露于固定浓度的达科替尼或不使用ENU长期暴露于不断增加浓度的达科替尼，建立耐药克隆。Sanger测序分析EGFR继发性突变。根据突变情况比较各无性系产生抗性的时间。利用逆转录病毒载体将EGFR Del19、L858R和G719A突变引入Ba/F3细胞。结果：长期暴露于dacomitinib而不使用ENU可诱导表达Del19的Ba/F3细胞中的T790M。ENU诱变产生171个耐达科米替尼克隆。在这些克隆中，90%获得了T790M。然而，使用低剂量dacomitinib建立的l858r突变克隆中有11%（35个中的4个）发生C797S， g719a突变克隆中有24%（38个中的12个）发生C797S。突变体T790M-和c797s -在L858R （p = 0.93）和G719A （p = 0.86）无性系间抗性时间差异不显著。获得T790M的表达Del19的细胞对奥希替尼敏感，而L858R + C797S突变的细胞对吉非替尼或厄洛替尼敏感。结论：这些体外数据表明，dacomitinib可直接诱导T790M或C797S继发性突变。我们的数据表明分析这些继发性突变的重要性，因为适当选择EGFR抑制剂可以克服肺癌亚群对dacomitinib的获得性耐药。(C) 2018年国际肺癌研究协会。Elsevier Inc.出版。版权所有。
Introduction: Dacomitinib was superior to gefitinib in terms of progression-free survival in patients with EGFR-mutant lung cancer in a recent ARCHER 1050 trial. However, despite a marked initial response, lung cancers eventually acquire resistance to these inhibitors. This study aimed to elucidate the mechanisms of acquired resistance to dacomitinib in vitro.Methods: Dacomitinib-resistant clones were established by exposure to fixed concentrations of dacomitinib by using N-ethyl- N-nitrosourea (ENU) mutagenesis or by chronic exposure to increasing concentrations of dacomitinib without ENU. EGFR secondary mutations were analyzed by Sanger sequencing. Time to resistance in each clone was compared according to the mutational status. EGFR Del19, L858R, and G719A mutations were introduced into Ba/F3 cells by using retroviral vectors.Results: Chronic exposure to dacomitinib without ENU induced T790M in Ba/F3 cells expressing Del19. ENU mutagenesis resulted in 171 dacomitinib-resistant clones. Among these clones, 90% acquired T790M. However, C797S occurred in 11% of L858R-mutant clones (four of 35) and in 24% of G719A-mutant clones (12 of 38) established by using low-dose dacomitinib. Time to resistance was not significantly different between T790M- and C797S-mutant clones in both of L858R clones (p = 0.93) and G719A clones (p = 0.86). Cells expressing Del19 that acquired T790M were sensitive to osimertinib, whereas cells with L858R plus C797S mutations were sensitive to gefitinib or erlotinib.Conclusions: These in vitro data demonstrate that dacomitinib can directly induce T790M or C797S secondary mutations. Our data suggest the importance of analyzing these secondary mutations because appropriate selection of EGFR inhibitors could overcome acquired resistance to dacomitinib in a subset of lung cancers. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.