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    New molecules to treat HER2-positive breast cancers and brain metastases

    Team Sandrine Bourdoulous

    New molecules to treat HER2-positive breast cancers and brain metastases

     

    In this article, published in Cancer Research journal, the team of Sandrine Bourdoulous has shown that Moesin interacts with the oncogene HER2 and keeps it in an inactive state. In some cancers ("HER2-positive"), expression level of Moesin is low. Researchers have identified Moesin-mimicking compounds (such as zuclopenthixol) and show that they could enable the targeting of HER2-positive breast cancers and their derived brain metastases.

     

    From 20 to 30% breast cancers present aberrant expression of HER2, a tyrosine kinase receptor stimulating tumor cell proliferation and survival. These so-called HER2+ breast cancers are aggressive and are associated with poor prognosis. These last years, the development of HER2-targeted therapies based on the use of monoclonal antibodies or tyrosine kinase inhibitors has significantly improved the prognosis of these cancers. However, HER2+ tumor cells still too often escape these treatments by setting up resistance mechanisms, for example by promoting the expression of truncated or mutated forms of this receptor, which are resistant to current treatments. Another limitation resides in their poor ability of these treatments to cross the blood-brain barrier, conditioning the targeting of cerebral metastases, which affect up to 50% of patients treated for metastatic HER2+ breast cancers. The major challenge therefore remains the identification of effective therapeutic agents against resistant forms of HER2 and brain metastases from HER2+ breast cancers.

     

    In this study, the authors demonstrate that HER2 receptor possesses, in a region not yet targeted by current therapies, a binding motif to ERMs proteins (Ezrin, Radixin and Moesin) which make, in vivo, the link between membrane proteins and the cell skeleton. The ERMs keep HER2 in an inactive state. In HER2+ breast cancers, the expression of Moesin is greatly reduced. To compensate for this decrease, the authors designed a high-throughput screen based on HER2/ERM interaction to identify a chemical compound able to mimic the inhibitory effects of ERMs on HER2. They identified Zuclopenthixol, an antipsychotic drug currently used in humans to reduce hallucinations and for its sedative effects. Using normal or breast cancer cell lines, the scientists have shown that Zuclopenthixol, or its analog compound Flupenthixol, inhibits HER2 activation, including its mutated and truncated forms. Using an orthotopic xenograft mouse model, they further demonstrate that it blocks tumor progression of HER2+ cancers, and significantly attenuates the growth of HER2+ tumors implanted in the brain.

     

    This work shows that Moesin-mimicking compounds, such as zuclopenthixol, constitute a new class of HER2 inhibitors, active both on HER2+ primary tumors and brain metastases, and which could provide significant benefit for the treatment of these cancers.

     

    Figure legend: In physiological conditions, Moesin keeps HER2 receptor in an inactive state. In HER2+ mammary tumors, the repression of Moesin expression combined to HER2 overexpression exacerbates HER2 activation, proliferation and survival of tumor cells. Treatment with a Moesin-mimicking compound blocks the progression of HER2+ mammary tumor and brain metastases.

    © Camille Faure & Sandrine Bourdoulous

     

    Reference

    Allosteric inhibition of HER2 by Moesin-mimicking compounds targets HER2-positive cancers and brain metastases. Camille Faure, Rym Djerbi-Bouillié, Anaïs Domingot, Haniaa Bouzinba-Segard, Saïd Taouji, Yanis Saidi, Sandra Bernard, Floriane Carallis, Romy Rothe-Walther, Jean-Luc Lenormand, Eric Chevet and Sandrine Bourdoulous. Cancer Res. September 7 2021.  DOI:10.1158/0008-5472.CAN-21-0162.

     

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