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Anti-Epidermal Growth Factor Vaccine Antibodies Enhance the Efficacy of Tyrosine Kinase Inhibitors and Delay the Emergence of Resistance in EGFR Mutant Lung Cancer Cells
Journal of Thoracic Oncology ( IF 20.4 ) Pub Date : 2018-09-01 , DOI: 10.1016/j.jtho.2018.04.030
Jordi Codony-Servat , Silvia García-Roman , Miguel Ángel Molina-Vila , Jordi Bertran-Alamillo , Ana Giménez-Capitán , Santiago Viteri , Andrés F Cardona , Erik D’Hondt , Niki Karachaliou , Rafael Rosell

Introduction: Mutations in EGFR correlate with impaired response to immune checkpoint inhibitors and the development of novel immunotherapeutic approaches for EGFR mutant NSCLC is of particular interest. Immunization against epidermal growth factor (EGF) has shown efficacy in a phase III trial including unselected NSCLC patients, but little was known about the mechanisms involved in the effects of the anti‐EGF antibodies generated by vaccination (anti‐EGF VacAbs) or their activity in tumor cells with EGFR mutations. Methods: The EGFR‐mutant, NSCLC cell lines H1975, and PC9, together with several gefitinib and osimertinib‐resistant cells derived from PC9, were treated with anti‐EGF VacAbs and/or EGFR tyrosine kinase inhibitors (TKIs). Cell viability was analyzed by proliferation assays, cell cycle by fluorescence‐activated cell sorting analysis, and levels of RNA and proteins by quantitative retro‐transcription polymerase chain reaction and Western blotting. Results: Anti‐EGF VacAbs generated in rabbits suppressed EGF‐induced cell proliferation and cycle progression and inhibited downstream EGFR signaling in EGFR‐mutant cells. Sera from patients immunized with an EGF vaccine were also able to block activation of EGFR effectors. In combination, the anti‐EGF VacAbs significantly enhanced the antitumor activity of all TKIs tested, suppressed Erk1/2 phosphorylation, blocked the activation of signal transducer and activator of transcription 3 (STAT3) and downregulated the expression of AXL receptor tyrosine kinase (AXL). Finally, anti‐EGF VacAbs significantly delayed the emergence in vitro of EGFR TKI resistant clones. Conclusions: EGFR‐mutant patients can derive benefit from immunization against EGF, particularly if combined with EGFR TKIs. A phase I trial of an EGF vaccine in combination with afatinib has been initiated.

中文翻译:

抗表皮生长因子疫苗抗体增强酪氨酸激酶抑制剂的功效并延缓 EGFR 突变肺癌细胞耐药性的出现

简介:EGFR 突变与对免疫检查点抑制剂的反应受损相关,开发针对 EGFR 突变 NSCLC 的新型免疫治疗方法尤其令人感兴趣。针对表皮生长因子 (EGF) 的免疫接种已在包括未选择的 NSCLC 患者在内的 III 期试验中显示出疗效,但对疫苗接种产生的抗 EGF 抗体(抗 EGF VacAbs)或其活性所涉及的机制知之甚少在具有 EGFR 突变的肿瘤细胞中。方法:用抗 EGF VacAb 和/或 EGFR 酪氨酸激酶抑制剂 (TKI) 处理 EGFR 突变的 NSCLC 细胞系 H1975 和 PC9,以及源自 PC9 的几种吉非替尼和奥希替尼耐药细胞。通过增殖分析分析细胞活力,通过荧光激活细胞分选分析分析细胞周期,通过定量逆转录聚合酶链反应和蛋白质印迹法检测 RNA 和蛋白质的水平和水平。结果:兔体内产生的抗 EGF VacAb 抑制了 EGF 诱导的细胞增殖和周期进程,并抑制了 EGFR 突变细胞中的下游 EGFR 信号传导。来自用 EGF 疫苗免疫的患者的血清也能够阻断 EGFR 效应子的激活。联合使用抗 EGF VacAb 可显着增强所有测试的 TKI 的抗肿瘤活性,抑制 Erk1/2 磷酸化,阻断信号转导和转录激活因子 3 (STAT3) 的激活,并下调 AXL 受体酪氨酸激酶 (AXL) 的表达. 最后,抗 EGF VacAb 显着延迟了体外 EGFR TKI 抗性克隆的出现。结论:EGFR 突变患者可以从针对 EGF 的免疫接种中获益,特别是如果与 EGFR TKI 联合使用。EGF 疫苗联合阿法替尼的 I 期试验已经启动。
更新日期:2018-09-01
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