Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients

Abstract

The phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway that has regulatory roles in cell survival, proliferation, and differentiation, and a critical role in tumorigenesis. In cancer, multiple studies have investigated the therapeutic targeting of the PI3K pathway, and multiple inhibitors targeting PI3K and its isoforms, protein kinase B/AKT, mammalian target of rapamycin (mTOR), and other pathway proteins have been developed. For the treatment of solid tumors, only allosteric mTOR inhibitors, such as everolimus and temsirolimus, are currently approved for clinical use. This review describes the PI3K inhibitors that have progressed from the laboratory to late-stage clinical trials, and discusses the challenges that have prevented other compounds from doing the same. Challenges to the therapeutic effectiveness of some PI3K inhibitors include the absence of reliable and effective biomarkers, their limited efficacy as single agents, insufficient development of rational therapeutic combinations, the use of schedules with a variety of off-target effects, and suboptimal therapeutic exposures. Therefore, with regard to PI3K inhibitors currently in late-stage clinical trials, the identification of appropriate biomarkers of efficacy and the development of optimal combination regimens and dosing schedules are likely to be important for graduation into clinical practice.

Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

“…However, the promising clinical activity observed with buparlisib (despite only a 1.9‐month median duration of exposure to buparlisib in BELLE‐2) suggests there could be a place for PI3K inhibitors in the treatment of ABC if their associated toxicity could be reduced. Currently, isoform‐selective PI3K inhibitors are under clinical development and may offer efficacy benefits while avoiding some off‐target toxicities seen with pan‐PI3K inhibitors .…”

Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells

“…The PI3K/Akt pathway plays an important role in many cellular processes, such as cell survival, proliferation, migration, differentiation, and tumorigenesis [39][40][41]. Several studies have indicated that aberrant activation of the PI3K/Akt pathway is found in many human cancers, including colorectal cancer [20,42].…”

In Vitro and in Vivo antitumor activity and the mechanism of siphonodictyal B in human colon cancer cells

“…Furthermore, both liphagal and siphonodictyal B have been reported to exert inhibitory activity against phosphatidylinositol 3‐kinase (PI3K), a lipid kinase that converts phosphatidylinositol 4,5‐bisphosphate to phosphatidylinositol 3,4,5‐triphosphate (PIP3). PIP3 in turn activates protein kinase B (AKT) and downstream molecules, leading to the promotion of cell growth, proliferation, and survival . In many types of cancer cells, the PI3K‐AKT pathway is frequently activated through gain‐of‐function mutations in PIK3CA, which encodes p110 α , the catalytic subunit of PI3K .…”

“…PIP3 in turn activates protein kinase B (AKT) and downstream molecules, leading to the promotion of cell growth, proliferation, and survival. 7 In many types of cancer cells, the PI3K-AKT pathway is frequently activated through gain-of-function mutations in PIK3CA, which encodes p110α, the catalytic subunit of PI3K. 8 Therefore, PI3K is considered a potential drug target for cancer therapy.…”