EPHA2 blockade reverses acquired resistance to afatinib induced by EPHA2-mediated MAPK pathway activation in gastric cancer cells and avatar mice.
EPHA2 阻断逆转胃癌细胞和阿凡达小鼠中 EPHA2-mediated MAPK 通路激活诱导的对阿法替尼的获得性耐药性。
EPHA2 acquired resistance afatinib gastric cancer patient-derived xenograft
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摘要

Afatinib is a pan-HER inhibitor approved for specific types of lung cancer. We explored antitumor activity, predictive biomarkers and the potential mechanisms underlying antitumor effect and acquired resistance of afatinib in gastric cancer (GC) in vitro and in vivo. Five human GC cell lines and eight patient-derived xenograft (PDX) models with clear molecular profiling were used to evaluate the antitumor activity and mechanisms of afatinib. The ErbB family and downstream PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) pathways were evaluated before and after afatinib treatment. An afatinib-resistant PDX model was established to explore both the potential mechanisms of drug resistance and reversal strategies. We found that afatinib exerted a strong tumor suppression in EGFR/HER2 highly amplified (copy number >6) or overexpressed (IHC 3+) PDX models and a moderate tumor suppression in EGFR/HER2 moderately expressed (IHC 2+) PDX models. Afatinib selectively inhibited the proliferation of HER2 highly amplified GC cells in a dose-dependent manner in vitro. Afatinib also exerted its antitumor effect by inducing cell apoptosis and cell arrest at G1 phase. Diminished activation of the ErbB family and downstream PI3K/AKT/mTOR and MAPK pathways was also observed. Erythropoietin-producing hepatocellular receptor A2 (EPHA2) upregulation and phosphorylation might be involved in afatinib-acquired resistance, and EPHA2 blockade could restore afatinib sensitivity. GC patients with amplification (copy number >6) or overexpression (IHC 3+) of EGFR/HER2 were most likely to benefit from afatinib treatment and EPHA2 blockade reversed acquired resistance to afatinib treatment, which could provide solid evidences for future clinical trials.

译文

阿法替尼是一种被批准用于特定类型肺癌的泛 HER 抑制剂。我们探索了阿法替尼在胃癌 (GC) 体内和体外的抗肿瘤活性、预测生物标志物和潜在机制。使用 5 种具有清晰分子谱的人类 GC 细胞系和 8 种患者来源的异种移植 (PDX) 模型来评估阿法替尼的抗肿瘤活性和机制。在阿法替尼治疗前后评估了 ErbB 家族和下游 PI3K/AKT/mTOR 和丝裂原活化蛋白激酶 (MAPK) 通路。建立阿法替尼耐药的 PDX 模型,以探索耐药的潜在机制和逆转策略。我们发现阿法替尼在 EGFR/HER2 高度扩增 (拷贝数> 6) 或过度表达 (IHC 3) 中发挥了强烈的肿瘤抑制作用 PDX 模型和 EGFR/HER2 中度表达 (IHC 2) PDX 模型中的中度肿瘤抑制。阿法替尼在体外以剂量依赖性方式选择性抑制 HER2 高扩增 GC 细胞的增殖。阿法替尼还通过诱导细胞凋亡和 G1 期细胞阻滞发挥其抗肿瘤作用。还观察到 ErbB 家族和下游 PI3K/AKT/mTOR 和 MAPK 通路的激活减弱。产生红细胞生成素的肝细胞受体 A2 (EPHA2) 的上调和磷酸化可能参与阿法替尼的获得性抵抗,EPHA2 阻断可以恢复阿法替尼的敏感性。有 EGFR/HER2 扩增 (拷贝数> 6) 或过表达 (IHC 3) 的 GC 患者最有可能从阿法替尼治疗和 EPHA2 阻断逆转阿法替尼治疗的获得性耐药性中获益, 这可以为未来的临床试验提供坚实的证据。

afatinib

肿瘤 肺癌 药物
概述  :  

阿法替尼是表皮生长因子受体(EGFR)和人表皮生长因子受体2(HER2)酪氨酸激酶的强效、不可逆的双重抑制剂。本品适用于以下患者治疗:具有表皮生长因子受体基因敏感突变的局部晚期或转移性非小细胞肺癌,既往未接受过EGFR酪氨酸激酶抑制剂(TKI)治疗;含铂化疗期间或化疗后疾病进展的局部晚期或转移性鳞状组织学类型的非小细胞肺癌。阿法替尼与EGFR酪氨酸激酶区的结合是不可逆性的,所以阿法替尼相比一代药的效果更强,但是就是因为效果更强,所以副作用也更大,而且阿法替尼对ErbB4的信号通路也有抑制作用

Afatinib 

释    义   n. 阿法替尼;妥复克

例    句   Afatinib is an investigational orally administered irreversible inhibitor of both the epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases. Afatinib是一种口服且作用不可逆的内皮生长因子受体(EGFR)及人类表皮受体2(HER2)酪氨酸激酶抑制剂。

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