The potential for inhibition of HER2 dimerization: a novel approach

Current HER2-targeted strategies are not designed to inhibit HER2 receptor ligand-induced dimerization, thus potentially allowing for continued HER signaling.⁷

Mechanistically, HER2 Dimerization Inhibitors (HDIs) are designed to inhibit the formation of HER2 dimers, including HER2:HER3 dimers.⁵ Preclinical studies suggest that inhibiting this dimer pair interrupts both the MAPK cell proliferation pathway and the PI3K cell survival pathway and, ultimately, tumor growth.¹ Targeting the dimerization sub-domain of HER2 may be a novel approach for patients with HER2+ disease, because it has the potential to more comprehensively inhibit multiple signaling pathways in the HER network.⁷

Preclinical studies further indicate that progression on currently available HER2-targeted strategies may be due to incomplete inhibition of the HER signaling network. Results show that using HER2 Dimerization Inhibitors (HDIs) with other HER2-targeted approaches leads to a more comprehensive blockade of signaling.¹