V-ATPase inhibition overcomes trastuzumab resistance in breast cancer.
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.
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, 81377 Munich, Germany. Electronic address: karin.von.schwarzenberg@cup.uni-muenchen.de.
Karin
K
von Schwarzenberg
Department of Biophysics and Cell Biology, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
Tamás
T
Lajtos
Department of Biophysics and Cell Biology, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
Làszló
L
Simon
Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, PO 151150, 66041 Saarbrücken, Germany.
Rolf
R
Müller
Department of Biophysics and Cell Biology, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary; MTA Cell Biology and Signaling Research Group, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
György
G
Vereb
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, 81377 Munich, Germany.
Angelika M
AM
Vollmar
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000068878:Trastuzumab; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D025262:Vacuolar Proton-Translocating ATPases
Breast cancer; Endocytosis; HER2; Trastuzumab; V-ATPase