The PI3K/AKT/mTOR Signaling Pathway: Implications in the Treatment of Breast Cancer

Abstract

Epidemiologic and experimental studies support a key role of the phosphatidyl inositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in the biology of human cancers. Alterations resulting in activation of PI3K/Akt/mTOR signaling are perhaps the most frequent events observed in solid tumors, including breast cancer, and contribute to neoplastic transformation. The PI3K/mTOR pathway can be activated by overproduction of growth factors or chemokines, loss of phosphatase and tensin homolog (PTEN) expression, or by mutations in growth factor receptors Ras, PTEN, or PI3K itself. Activation of this pathway contributes to cell cycle proliferation, growth, cell cycle entry, survival, cell motility, protein synthesis, and glucose metabolism, all important aspects of tumorigenesis. The most common genetic aberrations in breast cancer are activating somatic missense mutations in the gene encoding the p110a (PIK3CA) subunit of PI3K. The PTEN gene is often hypermethylated or decreased in expression, through as yet unclear mechanisms, in breast cancer. Studies have shown that PI3K/PTEN/AKT pathway modulation is implicated in HER2/neu-tumorigenesis and in response to the HER2-targeting antibody trastuzumab. Components of the pathway are regulated by feed-back and cross-talk to other signaling cascades and appear to be implicated with drug resistance. Over the past few years, a number of components of this signaling cascade have been the subject of intense drug-discovery activities. Rapamycin analogs have already been shown to have antitumor efficacy in some tumor types. Newer-generation PI3K, AKT, and mTOR inhibitors have shown significant promise preclinically and are now in clinical trials. This article summarizes the progress made in the elucidation of the pathway, clinical implications in pathology of breast cancer, and reviews novel drugs targeting this pathway for cancer treatment, particularly inhibitors of PI3K, AKT, and mTOR, currently undergoing clinical trials. Potential combination strategies, safety concerns, and resistance mechanisms for this new generation of anticancer agents are also discussed.