HER2-positive breast cancer, defined by amplification of the ERBB2 oncogene and/or overexpression of the HER2 receptor tyrosine kinase, accounts for approximately 20–25% of breast cancers and is characterized by an aggressive phenotype and poor prognosis. The advent of targeted therapies—antibodies such as trastuzumab and pertuzumab, or tyrosine kinase inhibitors such as lapatinib—has markedly improved patient survival. However, primary or acquired resistance persists, as does cardiotoxicity. Nearly 30% of HER2-positive tumors express a truncated form of the receptor (p95HER2) that confers resistance to trastuzumab, and activating somatic mutations can likewise evade treatment. Finally, these molecules cross the blood–brain barrier poorly and remain of limited efficacy against brain metastases, which occur in up to half of patients treated with trastuzumab.
The authors report that, unlike the other receptors of the HER family, HER2 harbors in its cytosolic juxtamembrane region a motif for direct interaction with proteins of the Ezrin/Radixin/Moesin (ERM) family. Under physiological conditions, this interaction confines HER2 to membrane domains enriched in ERM proteins and maintains it in a catalytically repressed state, preventing its ligand-independent activation. In HER2-positive breast tumors, low Moesin expression correlates with HER2 overexpression, and this inverse correlation has been observed across several cancer types (breast, cervix, stomach, bladder, pancreas, colon, ovary, kidney). Restoring ERM protein expression in cancer cells is sufficient to reverse HER2 activation and to inhibit HER2-dependent proliferation. ERM proteins thus emerge as allosteric regulators of HER2 activation.
Using a high-throughput assay reproducing the HER2–ERM interaction, a library of approximately 1,500 approved drugs was screened. This screen identified zuclopenthixol, a thioxanthene-class neuroleptic used to treat certain psychiatric disorders, which behaves as a Moesin-mimetic compound: it binds directly to the juxtamembrane region of HER2 and blocks its activation, including for the truncated p95HER2 form and oncogenic mutant forms (V777L, V842I) resistant to existing treatments. The authors note that this effect is independent of neuroleptic activity, since the related flupenthixol produces comparable effects whereas chlorprothixene does not interact with HER2.
Zuclopenthixol reduces tumor progression in vitro and in vivo and, being able to rapidly penetrate the brain, exerts significant activity against brain tumors derived from HER2-positive cancers (p = 0.0112 in a murine intracerebral xenograft model). This work defines a new class of allosteric HER2 inhibitors and provides proof of concept that a Moesin-mimetic compound could complement current targeted therapies for the treatment of HER2-positive cancers and their brain metastases.