The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer.
The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer.
复制标题
DOI：
10.18632/oncotarget.5286
复制
发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Nakagawa K
中科院分区：
文献类型：
--
作者：
Yonesaka K;Kudo K;Nishida S;Takahama T;Iwasa T;Yoshida T;Tanaka K;Takeda M;Kaneda H;Okamoto I;Nishio K;Nakagawa K
阿法替尼是第二代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），其特征是不可逆的泛人EGFR（HER）家族抑制剂。阿法替尼对第一代EGFF-TKI（如厄洛替尼）获得性耐药的非小细胞肺癌（NSCLC）患者亚群仍有效。调蛋白以自分泌方式激活HER 3并导致NSCLC中的厄洛替尼耐药。在此，我们研究了阿法替尼是否对携带EGFR激活突变的调蛋白过表达NSCLC有效。在体外和小鼠异种移植物中，阿法替尼（而非厄洛替尼）可降低EGFR突变型NSCLC PC 9 HRG细胞增殖。阿法替尼可抑制细胞信号通路蛋白HER 3、EGFR、HER 2和HER 4的磷酸化，可能是通过阻止转磷酸化，因为HER 3激酶活性不足以进行自磷酸化。与厄洛替尼不同，阿法替尼抑制AKT活化，导致PC 9 HRG细胞凋亡增加。在临床上，与健康志愿者相比，33例接受第一代EGFR-TKI治疗的EGFR突变和NSCLC患者亚群显示血浆调蛋白水平升高;其中1例患者尽管既往发生厄洛替尼耐药，但在阿法替尼治疗后仍达到缓解。阿法替尼可克服EGFR突变型NSCLC中heregulin介导的厄洛替尼耐药。需要进一步研究以确定heregulin是否可以预测第一代EGFR-TKI耐药后阿法替尼的疗效。
Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.