Allosteric inhibition of HER2 by Moesin-mimicking compounds targets HER2-positive cancers and brain metastases - Institut du Fer à Moulin Accéder directement au contenu
Article Dans Une Revue Cancer Research Année : 2021

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

Résumé

Therapies targeting the tyrosine kinase receptor HER2 have significantly improved survival of patients with HER2 cancer. However, both 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 and 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.
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Dates et versions

hal-03361201 , version 1 (21-12-2021)

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Camille Faure, Rym Djerbi-Bouillié, Anaïs Domingot, Haniaa Bouzinba-Segard, Saïd Taouji, et al.. Allosteric inhibition of HER2 by Moesin-mimicking compounds targets HER2-positive cancers and brain metastases. Cancer Research, 2021, 81 (21), pp.5464-5476. ⟨10.1158/0008-5472.CAN-21-0162⟩. ⟨hal-03361201⟩
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