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.
Highlights
Phosphoinositide 3-kinase (PI3K) is a group of lipid kinases that phosphorylate the30 -OH group of phosphatidylinositol (PI) at plasma and intracellular membranes
PIP3 is mainly produced at the plasma membrane in response to different stimuli and allows for the recruitment of a myriad of phospholipid effectors, including serine/threonine kinase AKT and 3-phosphoinositidedependent protein kinase-1 (PDK-1), which are the central mediators of the PI3K pathway
Buparlisib safety and efficacy was assessed in two large phase III randomized clinical trials called BELLE-2 and BELLE-During the BELLE-2 clinical trial, either buparlisib or placebo was administered in combination with fulvestrant to treat post-menopausal women with HR+/HER- metastatic breast cancer who had been previously treated or who had progressed on treatment with an aromatase inhibitor (AI) and up to one previous line of chemotherapy for advanced disease [67]
Summary
Phosphoinositide 3-kinase (PI3K) is a group of lipid kinases that phosphorylate the. 30 -OH group of phosphatidylinositol (PI) at plasma and intracellular membranes. Besides mutations in PIK3CA and PIK3CB genes, inactivating events occur in tumor suppressors such as PTEN (Cancer Genome Atlas, 2012). In addition to PTEN, inositol polyphosphate4-phosphatase type IIB (INPP4B) can counteract PI3KCA signaling, and loss of its genetic locus has been reported in breast cancer [40,41]. Recent findings suggest that INPP4B facilitates PI3KCA crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2-to-PI(3)P conversion on late endosomes, suggesting that these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies [43]. Activating mutations in AKT1 occur in nearly 4% of Luminal [19,44], and genetic amplifications of AKT2 and PDK1 are observed in all breast cancer subtypes with a frequency of 3% and 20–38%, respectively [45,46]. In the following paragraphs we will describe the clinical development and efficacy of different PI3K inhibitors for breast cancer treatment
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