Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications

Abstract

The combination of a PI3K inhibitor with trastuzumab has been shown to be effective at overcoming trastuzumab resistance in models of HER2(+) breast cancer by inhibiting HER2-PI3K-FOXO-survivin signaling. In this review the potential clinical implications of these findings are discussed.

©2013 AACR.

Figures

Figure. Inhibition of the HER2-PI3K-FOXO-survivin axis by trastuzumab and PI3K inhibitors

Blockade of HER2 by trastuzumab along with PI3K inhibitors in trastuzumab-sensitive and -resistant cells results in inactivation of Akt. This results in hypophosphorylation of FOXO transcription factors which, in turn, translocate to the nucleus where they repress transcription of IL-8 and survivin. The end result is loss of maintenance of cancer stem cells and antiapoptotic proteins such as survivin.