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.
