V-ATPase inhibition overcomes trastuzumab resistance in breast cancer

Karin von Schwarzenberg, Tamás Lajtos, Làszló Simon, Rolf Müller, G. Vereb, Angelika M. Vollmar

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)9-19
Number of pages11
JournalMolecular Oncology
Volume8
Issue number1
DOIs
Publication statusPublished - Feb 2014

Fingerprint

Vacuolar Proton-Translocating ATPases
Breast Neoplasms
Recycling
Neoplasms
Growth
Apoptosis
Endosomes
Drug Delivery Systems
Lysosomes
Oncogenes
Heterografts
Cytosol
Therapeutics
Cell Membrane
Trastuzumab
Cell Line
Survival

Keywords

  • Breast cancer
  • Endocytosis
  • HER2
  • Trastuzumab
  • V-ATPase

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

von Schwarzenberg, K., Lajtos, T., Simon, L., Müller, R., Vereb, G., & Vollmar, A. M. (2014). V-ATPase inhibition overcomes trastuzumab resistance in breast cancer. Molecular Oncology, 8(1), 9-19. https://doi.org/10.1016/j.molonc.2013.08.011

V-ATPase inhibition overcomes trastuzumab resistance in breast cancer. / von Schwarzenberg, Karin; Lajtos, Tamás; Simon, Làszló; Müller, Rolf; Vereb, G.; Vollmar, Angelika M.

In: Molecular Oncology, Vol. 8, No. 1, 02.2014, p. 9-19.

Research output: Contribution to journalArticle

von Schwarzenberg, K, Lajtos, T, Simon, L, Müller, R, Vereb, G & Vollmar, AM 2014, 'V-ATPase inhibition overcomes trastuzumab resistance in breast cancer', Molecular Oncology, vol. 8, no. 1, pp. 9-19. https://doi.org/10.1016/j.molonc.2013.08.011
von Schwarzenberg, Karin ; Lajtos, Tamás ; Simon, Làszló ; Müller, Rolf ; Vereb, G. ; Vollmar, Angelika M. / V-ATPase inhibition overcomes trastuzumab resistance in breast cancer. In: Molecular Oncology. 2014 ; Vol. 8, No. 1. pp. 9-19.
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