Abstract
The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates several cellular processes and it’s one of the most frequently deregulated pathway in human tumors. Given its prominent role in cancer, there is great interest in the development of inhibitors able to target several members of PI3K signaling pathway in clinical trials. These drug candidates include PI3K inhibitors, both pan- and isoform-specific inhibitors, AKT, mTOR, and dual PI3K/mTOR inhibitors. As novel compounds progress into clinical trials, it’s becoming urgent to identify and select patient population that most likely benefit from PI3K inhibition. In this review we will discuss individual PIK3CA mutations as predictors of sensitivity and resistance to targeted therapies, leading to use of novel PI3K/mTOR/AKT inhibitors to a more “personalized” treatment.
Highlights
Over the past years, it has become widely accepted that cancer is a multistep genetic disease that arises by the activation of specific oncogenes, inactivation of tumor suppressor genes, and stochastic accumulation of genetic alterations driving tumor progression (Vogelstein and Kinzler, 2004)
Despite the genetic and epigenetic complexity observed in cancer, tumor growth and survival can be impaired by the inactivation of a single oncogene
In summary, available dataset showed that a high percentage of tumors harboring PIK3CA will likely benefit from inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway, a substantial proportion of patients with PIK3CA activating mutations may be de novo resistant to these agents
Summary
It has become widely accepted that cancer is a multistep genetic disease that arises by the activation of specific oncogenes, inactivation of tumor suppressor genes, and stochastic accumulation of genetic alterations driving tumor progression (Vogelstein and Kinzler, 2004). Several promising pan-PI3K inhibitors are under development and evaluation in clinical trials for cancer therapy These molecules predominantly display cytostatic effects with consequent G1 phase arrest in vitro and favorable anticancer effects in vivo. A second group of PI3K inhibitors has been developed to overcome the toxicity displayed by the treatment with panPI3K inhibitors They are characterized by greater selective activity (isoform-specific) and several molecules are currently under evaluation in preclinical and clinical studies. Since PI3K and mTOR share several structural similarities, many chemical compounds, under evaluation in clinical trials, are able to inhibit both catalytic subunits This third group of inhibitors is termed “dual PI3K/mTOR” and they have the advantage of inhibiting all class I isoforms and mTORC1 and mTORC2 having a strongest effectiveness in switching off the PI3K signaling pathway. Given the growing interest in inhibiting PI3K signaling pathway, the drug development landscape is becoming increasingly crowded and highly competitive, so that several pharmaceutical companies, such as Novartis, Sanofi-Aventis, Roche/Genentech, Bayer, and GlaxoSmithKline, are currently in competition to FIGURE 1 | Schematic representation of PI3K pathway and sites of action of PI3K signaling pathway inhibitors in solid tumors and hematological malignancies
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