Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer.

Abstract

Simple SummaryPI3K signaling pathway plays an essential role in many cellular processes and is frequently altered in breast cancer, leading to increased tumor growth and reduced survival. Small molecule inhibitors have been developed that target the three key elements of this pathway: PI3K, AKT, and mTOR. Despite demonstrating promising preclinical activity, intrinsic and acquired resistance, as well as high levels of adverse reactions, partially limited the therapeutic efficacy of PI3K/AKT/mTOR inhibitors. To increase therapeutic benefit, drug combinations and schedules need to be explored to identify those with the highest efficacy and lowest toxicity rate. In addition, defining appropriate patient subpopulations, for either monotherapy or drug combinations, and identifying predictive biomarkers remain a challenge. Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer death in women worldwide. Although early diagnosis and cancer growth inhibition has significantly improved breast cancer survival rate over the years, there is a current need to develop more effective systemic treatments to prevent metastasis. One of the most commonly altered pathways driving breast cancer cell growth, survival, and motility is the PI3K/AKT/mTOR signaling cascade. In the past 30 years, a great surge of inhibitors targeting these key players has been developed at a rapid pace, leading to effective preclinical studies for cancer therapeutics. However, the central role of PI3K/AKT/mTOR signaling varies among diverse biological processes, suggesting the need for more specific and sophisticated strategies for their use in cancer therapy. In this review, we provide a perspective on the role of the PI3K signaling pathway and the most recently developed PI3K-targeting breast cancer therapies.