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Cancer Res ; 81(21): 5464-5476, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34493594

RESUMO

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.


Assuntos
Biomimética/métodos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Clopentixol/farmacologia , Regulação Neoplásica da Expressão Gênica , Proteínas dos Microfilamentos/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Regulação Alostérica , Animais , Apoptose , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Antagonistas de Dopamina/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Proteínas dos Microfilamentos/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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