Xi-Ping Zhang

Human epidermal growth factor receptor 2 (HER2/neu or HER2) has long been recognized as an attractive therapeutic target for breast cancer. The YVMA in-frame insertion at the residue G776 (G776^YVMA) of HER2 kinase domain is a frequently observed mutation that can largely shift drug sensitivity in targeted therapy of HER2-positive breast cancer. Here, the molecular mechanism and biological significance of tyrosine kinase inhibitor (TKI) response to HER2 G776^YVMA insertion were investigated in detail. An established protocol that integrated bioinformatics modeling and kinase inhibition assay was employed to examine the structural basis, energetic property, and biological implication underlying the intermolecular interaction between HER2 kinase domain and three representative TKIs, i.e. two FDA-approved drugs lapatinib and gefitinib as well as a pan-kinase inhibitor staurosporine. It was found that the insertion mutation can moderately sensitize lapatinib, but cannot influence the inhibitory capability of staurosporine essentially, suggesting that the two inhibitors exhibit differentiated selectivity between the wild-type HER2 (HER2^WT) and HER2 G776^YVMA (HER2^YVMA) variant. In addition, the gefitinib, which was originally developed as EGFR inhibitor, only possesses modest potency against its noncogate target HER2^WT, and the insertion can further impair the potency, causing a strong resistance for the agent to HER2^YVMA variant.