The impact of PI3K inhibitors on breast cancer cell and its tumor microenvironment

Abstract

The phosphoinositide 3-kinase (PI3K) pathway shows frequent aberrant alterations and pathological activation in breast cancer cells. While PI3K inhibitors have not achieved expectant therapeutic efficacy in clinical trials, and several studies provide promising combination strategies to substantially maximize therapeutic outcomes. Besides its direct impact on regulating cancer cells survival, PI3K inhibitors are also demonstrated to have an immunomodulatory impact based on the tumor microenvironment. Inhibition of the leukocyte-enriched PI3K isoforms may break immune tolerance and restore cytotoxic T cell activity by reprogramming the tumor microenvironment. In addition, PI3K inhibitors have pleiotropic effects on tumor angiogenesis and even induce tumor vascular normalization. In this review, we discuss the mechanism of PI3K inhibitor suppression of breast cancer cells and modulation of the tumor microenvironment in order to provide further thoughts for breast cancer treatment.

Keywords: Breast cancer; Combination therapy; PI3K; Pathway inhibitors; Tumor microenvironment.

Figure 1. The phosphoinositide 3-kinase pathway and inhibitors of the pathway in cancer.

Tumor promoters and suppressors are labeled in orange and green, respectively. Study sites: RTK, receptor tyrosine kinase; GPCR, G-protein-coupled receptor; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PDK1, phosphoinositide dependent kinase-1; PTEN, phosphatase and tensin homolog; INPP4B: inositol polyphosphate 4-phosphatase type II; mTORC, mammalian target of rapamycin complex; SK6, S6 kinase; 4EBP1, 4E-binding protein 1.