Allosteric inhibition of HER2 by Moesin-mimicking compounds targets HER2-positive cancers and brain metastases.

Therapies targeting the tyrosine kinase receptor HER2 have significantly improved survival of HER2+ cancer patients. However, both de novo and acquired resistance remain a challenge, particularly in the brain metastatic setting. Here we report that, unlike other HER tyrosine kinase receptors, HER2 possesses a binding motif in its cytosolic juxtamembrane region that allows interaction with members of the ezrin/radixin/moesin (ERM) family. Under physiological conditions, this interaction controls the localization of HER2 in ERM-enriched domains and stabilizes HER2 in a catalytically repressed state. In HER2+ breast cancers, low expression of moesin correlated with increased HER2 expression. Restoring expression of ERM proteins in HER2+ breast cancer cells was sufficient to revert HER2 activation and inhibit HER2-dependent proliferation. A high-throughput assay recapitulating the HER2/ERM interaction allowed for screening of about 1500 approved drugs. From this screen, Zuclopenthixol, an anti-psychotic drug that behaved as a moesin-mimicking compound, was found to directly bind the juxtamembrane region of HER2 and specifically inhibit HER2 activation in HER2+ cancers, as well as activation of oncogenic mutated and truncated forms of HER2. Zuclopenthixol efficiently inhibited HER2-positive breast tumor progression in vitro and in vivo and, more importantly, showed significant activity on HER2-positive brain tumor progression. Collectively, these data reveal a novel class of allosteric HER2 inhibitors, increasing the number of approaches to consider for intervention on HER2+ breast cancers and brain metastases.