Drugging PI3K in cancer: refining targets and therapeutic strategies

Abstract

HighlightsPI3K is an important target for innovative anticancer drug development and precision medicine.Over 30 small molecule PI3K inhibitors are currently in clinical trial testing.These drugs include dual PI3K/mTOR, pan-Class I PI3K and isoform-selective PI3K inhibitors.The PI3Kδ inhibitor idelalisib has received FDA approval for the treatment of B-cell malignancies.Drug resistance, patient selection and development of targeted combinations remain challenges.

PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers

“…Unfortunately, many inhibitors targeting this pathway have shown disappointing results in Phase II/III clinical trials, and this has been attributed to a small therapeutic window accompanied by on-target toxicity from inhibiting this pathway in normal tissues, as well as a lack of predictive biomarkers to better identify the patients that will respond (18,19).…”

PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models

“…The importance of these regulations is highlighted by a growing group of human neurogenetic diseases, including congenital brain malformations (3), amyotrophic lateral sclerosis (4), and Charcot-Marie-Tooth disease (5), that are associated with mutations in PIP-modifying enzymes. While class I PI3 kinase (PI3K) inhibitors have made an impact as anticancer agents (6), there are as yet no targeted therapeutics in the clinical arena for monogenetic disorders of PIP metabolism.…”

Inhibition of the α-Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic

“…The PI3K-PIP3 signaling pathway has been recognized to be crucial in tumorigenesis and has therefore stimulated efforts for oncology drug development (Samuels et al, 2004;Yap et al, 2015;Massacesi et al, 2016). Although a role for PI3K in cardiac hypertrophy and contractile activity has been investigated in detail (Shioi et al, 2000;Dorn and Force, 2005;Rossello et al, 2017), the effects of the PI3K-PIP3 pathway in cardiac electrical activity and arrhythmogenesis have only recently begun to be defined.…”

“…In this study, we used these reagents to identify the specific arrhythmogenic pathway in vitro. These findings not only dissect a novel arrhythmogenic pathway in drug-induced arrhythmias and possibly other clinical settings, but also have implications for development and use of PI3K inhibitors in cancer (Yap et al, 2015) (Massacesi et al, 2016).…”