EPHA2 and breast cancer: Furthermore, expression of kinase-deficient variants of EphA2 in breast cancer cells led to decreased tumor volume and increased tumor cell apoptosis [167]. In vivo studies have demonstrated that chronic trastuzumab treatment results in the phosphorylation of EphA2 through Src kinase, causing the activation of PI3K/Akt and MAPK pathways, which lead to trastuzumab resistance [12].