ABSTRACT
Introduction
The phosphatidylinositol-3-kinase (PI3K) pathway is a crucial intracellular signaling pathway involved in cell growth, proliferation, survival, and metabolism, which is aberrant in almost all types of cancer. Extensive research is dedicated to elucidating the mechanisms of action and developing PI3K inhibitors. However, only a small portion of the research has been successfully translated into clinical applications.
Areas covered
In this review, we present an overview of the pivotal role that the PI3K pathway plays in tumor development. We discuss the current landscape of PI3K inhibitors in preclinical and clinical trials, address the mechanisms of resistance to PI3K inhibition along with their associated toxic effects, and highlight significant advancements in preclinical research of this field.
Expert Opinion
Based on our study and comprehension of PI3K, we provide a recapitulation of the key lessons learned from the research process and propose potential measures for improvement that could prove valuable.
Disclaimer
As a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also.Article highlights
Phosphoinositide 3-kinases(PI3K) pathway plays a key role in regulating diverse cellular processes, including cell growth, motility, survival, metabolism, angiogenesis, and more. This review provides a relatively complete summary of the PI3K pathway about the role and mechanism.
The PI3K pathway appears abnormal in almost all cancers, such as lung, breast, endometrial, ovarian cancer. This review scrutinizes the dysregulation of the PI3K pathway in cancer development and progression.
The most prevalent abnormalities in the PI3K/Akt/mTOR pathway include PTEN loss, PI3K mutation or amplification, and Akt activation or somatic mutations. Many PI3K pathway-related inhibitors have been developed or are under development, and this review categorizes PI3K inhibitors as well as gives examples.
Regarding PI3K-related inhibitors, drug resistance and toxic effects are two major issues that require intense attention. This review points out the problems confronting PI3K pathway-related inhibitors.
Because the PI3K pathway plays an important role in cancer development and progression, an in-depth and extensive study of this pathway is necessary. This review points out the direction of research on the PI3K pathway.
Declaration of interests
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
A reviewer on this manuscript has disclosed they are a consultant for iOnctura (Geneva, Switzerland), Pharming (Leiden, the Netherlands), a shareholder of Open Orphan (Dublin, Ireland) and have in the past advised multiple companies on PI3K inhibitor development. They have also received speaker fees from Gilead (Foster City, US). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.
Acknowledgments
We are thankful to the National Science Foundation for Excellent Young Scholars and National Natural Science Foundation of China.