Abstract
The hyper-activation of the phosphoinositide (PI) 3-kinase signaling pathway is a hallmark of many cancers and overgrowth syndromes, and as a result, there has been intense interest in the development of drugs that target the various isoforms of PI 3-kinase. Given the key role PI 3-kinases play in many normal cell functions, there is significant potential for the disruption of essential cellular functions by PI 3-kinase inhibitors in normal tissues; so-called on-target drug toxicity. It is, therefore, no surprise that progress within the clinical development of PI 3-kinase inhibitors as single-agent anti-cancer therapies has been slowed by the difficulty of identifying a therapeutic window. The aim of this review is to place the cellular, tissue and whole-body effects of PI 3-kinase inhibition in the context of understanding the potential for dose limiting on-target toxicities and to introduce possible strategies to overcome these.
Highlights
Given their use in cancer and other pathologies, we suggest how we can use our understanding of PI 3-Kinases are Essential to LifePhosphoinositide 3-kinases (PI3Ks) function in health and disease to tailor the use of PI3K inhibitors and utilize combination therapies
The activation of the PI3K pathway in cancer has led to a huge investment in developing inhibitors targeting this pathway
Very few PI3K inhibitors have been approved for clinical use
Summary
Phosphoinositide 3-kinases (PI3Ks) play a critical role in pathways regulating cellular functions such as metabolism, growth and survival, cytoskeletal rearrangements and cell migration and are, essential to life [1]. They are clearly implicated in cancer, immune dysfunction and overgrowth syndromes and, as such, PI3K inhibitors have been the focus of anti-cancer therapeutic developments [2]. The aim of this review is to discuss the essential nature of PI3K actions in cellular and whole-body function and place the effects of PI3K inhibition in context, highlighting the dose-limiting impacts of these therapeutics. Given their use in cancer and other pathologies, we suggest how we can use our understanding of PI3K function in health and disease to tailor the use of PI3K inhibitors and utilize combination therapies
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