Direct Inhibition of PI3K in Combination with Dual HER2 Inhibitors is Required for Optimal Antitumor Activity in HER2+ Breast Cancer Cells

Amplification of the HER2 oncogene occurs in approximately 25% of human breast cancers and predicts response to therapies targeting human epidermal growth factor receptor 2 (HER2), including trastuzumab, a monoclonal antibody directed against HER2, and lapatinib, a tyrosine kinase inhibitor (TKI) of HER2 and epidermal growth factor receptor (EGFR) [1,2]. HER2 is a member of the ErbB family of receptor tyrosine kinases (RTKs), which form both homo-and heterodimers, resulting in the activation of downstream signaling pathways [3]. In HER2-amplified cancers, the heterodimer of HER2 with kinase-deficient HER3 is a major activator of phosphoinositide 3-kinase (PI3K)-Akt signaling, and HER3, when phosphorylated, can directly couple to the p85 subunit of PI3K [4]. HER2amplified tumors show significant reliance on PI3K-Akt signaling [5,6].