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 patients with HER2(+) cancer. 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 physiologic 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 1,500 approved drugs. From this screen, we found Zuclopenthixol, an antipsychotic drug that behaved as a Moesin-mimicking compound, because it directly binds the juxtamembrane region of HER2 and specifically inhibits HER2 activation in HER2(+) cancers, as well as activation of oncogenic mutated and truncated forms of HER2. Zuclopenthixol efficiently inhibited HER2(+) breast tumor progression in vitro and in vivo and, more importantly, showed significant activity on HER2(+) 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. Significance: This study demonstrates the functional role of Moesin in maintaining HER2 in a catalytically repressed state and provides novel therapeutic approaches targeting HER2(+) breast cancers and brain metastasis using Moesin-mimicking compounds.

Automated summary

Therapies targeting the tyrosine kinase receptor HER2 have significantly improved survival of patients with HER2(+) cancer. However, resistance remains a challenge, particularly in the brain metastatic setting. This study identifies a novel class of allosteric HER2 inhibitors, including a compound mimicking Moesin, which effectively inhibits HER2(+) breast tumor progression and shows significant activity on HER2(+) brain tumor progression.