von Schwarzenberg Karin, Lajtos Tamás, Simon Làszló, Müller Rolf, Vereb György, Vollmar Angelika M
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, 81377 Munich, Germany.
Department of Biophysics and Cell Biology, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
Mol Oncol. 2014 Feb;8(1):9-19. doi: 10.1016/j.molonc.2013.08.011. Epub 2013 Sep 5.
The HER2 oncogene targeting drug trastuzumab shows remarkable efficacy in patients overexpressing HER2. However acquired or primary resistance develops in most of the treated patients why alternative treatment strategies are strongly needed. As endosomal sorting and recycling are crucial steps for HER2 activity and the vacuolar H⁺-ATPase (V-ATPase) is an important regulator of endocytotic trafficking, we proposed that targeting V-ATPase opens a new therapeutic strategy against trastuzumab-resistant tumor cells in vitro and in vivo. V-ATPase inhibition with archazolid, a novel inhibitor of myxobacterial origin, results in growth inhibition, apoptosis and impaired HER2 pro-survival signaling of the trastuzumab-resistant cell line JIMT-1. This is accompanied by a decreased expression on the plasma membrane and accumulation of HER2 in the cytosol, where it colocalizes with endosomes, lysosomes and autophagosomes. Importantly, microscopic analysis of JIMT-1 xenograft tumor tissue of archazolid treated mice confirms the defect in HER2-recycling which leads to reduced tumor growth. These results suggest that V-ATPase inhibition by archazolid induces apoptosis and inhibits growth of trastuzumab-resistant tumor cells by retaining HER2 in dysfunctional vesicles of the recycling pathway and consequently abrogates HER2-signaling in vitro as well as in vivo. V-ATPase inhibition is thus suggested as a promising strategy for treatment of trastuzumab-resistant tumors.
靶向人表皮生长因子受体2（HER2）的致癌基因药物曲妥珠单抗在HER2过表达的患者中显示出显著疗效。然而，大多数接受治疗的患者会产生获得性或原发性耐药，因此迫切需要替代治疗策略。由于内体分选和再循环是HER2活性的关键步骤，而液泡H⁺-ATP酶（V-ATP酶）是内吞运输的重要调节因子，我们提出靶向V-ATP酶为体外和体内抗曲妥珠单抗耐药肿瘤细胞开辟了一种新的治疗策略。用源自粘细菌的新型抑制剂阿扎立得抑制V-ATP酶，可导致曲妥珠单抗耐药细胞系JIMT-1的生长抑制、凋亡及HER2促生存信号受损。这伴随着质膜上HER2表达的降低以及HER2在细胞质中的积累，在细胞质中它与内体、溶酶体和自噬体共定位。重要的是，对阿扎立得处理小鼠的JIMT-1异种移植肿瘤组织进行显微镜分析证实了HER2再循环缺陷，这导致肿瘤生长减缓。这些结果表明，阿扎立得抑制V-ATP酶可诱导凋亡并抑制曲妥珠单抗耐药肿瘤细胞的生长，方法是将HER2保留在再循环途径的功能失调囊泡中，从而在体外和体内消除HER2信号。因此，V-ATP酶抑制被认为是治疗曲妥珠单抗耐药肿瘤的一种有前景的策略。
