Abnormal expression of HER2 tyrosine kinase receptor, which stimulates tumor cell proliferation and survival, occurs in nearly 30% of breast cancer cases as well as in an elevated number of other cancer types (gastric cancers, ovarian cancers, pancreatic cancers, etc.). These so-called HER2+ tumors are particularly invasive and confer an unfavorable clinical prognosis. Treatments targeting HER2 using monoclonal antibodies (trastuzumab) or tyrosine kinase inhibitors (lapatinib) considerably improved the outcome of patients diagnosed with HER2+ cancers. Nevertheless, HER2+ cancer cells regularly bypass these therapies by developing resistance mechanisms, such as increasing the expression of altered forms of this receptor that are unresponsive to current treatments. Furthermore, these therapies are associated with significant adverse effects due to the targeting of HER2 physiological activation or non-specific inhibition of other tyrosine kinases. These limitations reinforce the need to develop new therapeutic approaches for HER2+ cancers.
The team previously demonstrated that the binding of ERM proteins (Ezrin, Radixin et Moesin) to the HER2 receptor juxtamembrane region stabilizes this latter in an inactive conformation. The researchers conceived a screen based on this interaction to identify new allosteric inhibitors of HER2
In the present article, the authors characterize a family of compounds coming from this screen: ebselen oxide and derivatives. They demonstrate that these compounds efficiently block HER2 activation by interacting with the ERM-binding motif located in HER2 cytosolic juxtamembrane region. Thus, ebselen oxide inhibits the proliferation of HER2+ breast, gastric and ovarian tumor cells and the progression of HER2+ breast tumors. Ebselen oxide demonstrates efficacy against truncated/mutated forms of HER2 displaying various degrees of resistance to current treatments.
Legend: In HER2+ tumors, HER2 over-expression exacerbates HER2 activation, resulting in tumor cell proliferation and survival. Ebselen oxide reduces the progression of HER2+ tumors by targeting the HER2 cytosolic juxtamembrane region and potentiates the effects of current anti-HER2 therapies relying on the use of monoclonal antibodies or kinase inhibitors (trastuzumab, lapatinib).
Moreover, ebselen oxide administration reduces HER2+ mammary tumoral progression in vivo in a model of orthotopic xenografts. Finally, the authors demonstrate that combining ebselen oxide to trastuzumab or to lapatinib produces additive effects on HER2 inhibition, allowing a lowering dosage of these treatments and de facto a reduction of their adverse effects.
These results show that ebselen oxide is a newly identified allosteric inhibitor of HER2 that could bring a substantial advantage for the treatment of HER2+ cancers in combination with current anti-HER2 therapeutic strategies.
Ebselen oxide and derivatives are new allosteric HER2 inhibitors for HER2-positive cancers. Lucas Blasquez, Haniaa Bouzinba-Segard, Sandrine Bourdoulous and Camille Faure. Mol Oncol. 2023 Mar 13. doi: 10.1002/1878-0261.13419. Online ahead of print. PMID: 36912768