Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells.
Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells.
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DOI：
10.3390/ijms19103069
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发表时间：
2018-10-08
影响因子：
5.6
通讯作者：
Tschan MP
中科院分区：
文献类型：
--
作者：
Janser FA;Adams O;Bütler V;Schläfli AM;Dislich B;Seiler CA;Kröll D;Langer R;Tschan MP
食管腺癌（EAC）是一种高致死性癌症类型，总体生存率低。20%至30%的EAC过表达人表皮生长因子受体2（Her2），一种促进细胞生长和增殖的跨膜受体酪氨酸激酶。Her2过表达乳腺癌和胃食管癌患者可能受益于Her2抑制剂。然而，治疗抵抗是有据可查的。由于自噬，一种溶酶体依赖性分解代谢过程，与癌症抗性机制有关，我们测试了自噬调节是否影响EAC中Her2抑制剂的敏感性。Her2阳性OE19 EAC细胞在用小分子Her2抑制剂拉帕替尼处理后显示出自噬通量的诱导。与亲本OE19（OE19 P）细胞相比，新产生的拉帕替尼抗性OE19（OE19 LR）细胞显示出增加的基础自噬通量。基于这些结果，我们测试了拉帕替尼与自噬抑制剂的组合是否有益。OE19 P在双重处理后显示出显著降低的细胞活力，而OE19 LR已经对单独的自噬抑制敏感。此外，使用免疫组织化学在未经治疗的EAC患者队列（n = 112）中研究了Her2状态和自噬标志物表达（LC 3B和p62）。在这里，没有显着的相关性Her2状态和表达的LC 3B和p62被found.Our数据表明，耐Her2定向治疗与较高的基础自噬水平，这本身并不与Her2状态。因此，我们提出自噬可能有助于EAC对Her2靶向治疗的获得性耐药性，并且Her2和自噬抑制的组合可能对EAC患者有益。
Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.
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影响因子：
30.8
作者：
Dulak, Austin M.;Stojanov, Petar;Peng, Shouyong;Lawrence, Michael S.;Fox, Cameron;Stewart, Chip;Bandla, Santhoshi;Imamura, Yu;Schumacher, Steven E.;Shefler, Erica;McKenna, Aaron;Carter, Scott L.;Cibulskis, Kristian;Sivachenko, Andrey;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Auclair, Daniel;Thompson, Kristin;Sougnez, Carrie;Onofrio, Robert C.;Guiducci, Candace;Beroukhim, Rameen;Zhou, Zhongren;Lin, Lin;Lin, Jules;Reddy, Rishindra;Chang, Andrew;Landrenau, Rodney;Pennathur, Arjun;Ogino, Shuji;Luketich, James D.;Golub, Todd R.;Gabriel, Stacey B.;Lander, Eric S.;Beer, David G.;Godfrey, Tony E.;Getz, Gad;Bass, Adam J.
通讯作者：
Bass, Adam J.
DOI：
10.4081/ejh.2015.2481
发表时间：
2015-05-05
期刊：
European journal of histochemistry : EJH
影响因子：
--
作者：
Schläfli AM;Berezowska S;Adams O;Langer R;Tschan MP
通讯作者：
Tschan MP
影响因子：
5.6
作者：
Chude CI;Amaravadi RK
通讯作者：
Amaravadi RK
影响因子：
6.4
作者：
Fichter, Christiane Daniela;Timme, Sylvia;Lassmann, Silke
通讯作者：
Lassmann, Silke
影响因子：
7.5
作者：
Langer, Rupert;Rauser, Sandra;Walch, Axel
通讯作者：
Walch, Axel