As HER2/HER3 heterodimer-mediated activation of PI3K-Akt-mTor has been considered the most important signaling pathway driving the development of breast cancer, and constitutive activation of this pathway identified as a major resistant mechanisms for trastuzumab resistance, combined inhibition of both HER2 and PI3K-Akt-mTor has been explored to overcome trastuzumab resistance [165,166]. This evidence concerns the gene ERBB3 and breast carcinoma.