Computer-Aided Targeting of the PI3K/Akt/mTOR Pathway: Toxicity Reduction and Therapeutic Opportunities

Abstract

The PI3K/Akt/mTOR pathway plays an essential role in a wide range of biological functions, including metabolism, macromolecular synthesis, cell growth, proliferation and survival. Its versatility, however, makes it a conspicuous target of many pathogens; and the consequential deregulations of this pathway often lead to complications, such as tumorigenesis, type 2 diabetes and cardiovascular diseases. Molecular targeted therapy, aimed at modulating the deregulated pathway, holds great promise for controlling these diseases, though side effects may be inevitable, given the ubiquity of the pathway in cell functions. Here, we review a variety of factors found to modulate the PI3K/Akt/mTOR pathway, including gene mutations, certain metabolites, inflammatory factors, chemical toxicants, drugs found to rectify the pathway, as well as viruses that hijack the pathway for their own synthetic purposes. Furthermore, this evidence of PI3K/Akt/mTOR pathway alteration and related pathogenesis has inspired the exploration of computer-aided targeting of this pathway to optimize therapeutic strategies. Herein, we discuss several possible options, using computer-aided targeting, to reduce the toxicity of molecularly-targeted therapy, including mathematical modeling, to reveal system-level control mechanisms and to confer a low-dosage combination therapy, the potential of PP2A as a therapeutic target, the formulation of parameters to identify patients who would most benefit from specific targeted therapies and molecular dynamics simulations and docking studies to discover drugs that are isoform specific or mutation selective so as to avoid undesired broad inhibitions. We hope this review will stimulate novel ideas for pharmaceutical discovery and deepen our understanding of curability and toxicity by targeting the PI3K/Akt/mTOR pathway.

Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies

“…It will be important to incorporate and utilize the experience from oncology in using PI3K/AKT/mTOR inhibitors to treat cancer when considering clinical trials that may use these drugs for targeted treatment of segmental overgrowth disorders [Li and Wang, ; Porta et al, ; Yu et al, ]. In 2014, there were more than 50 drugs inhibiting the PI3K/AKT/mTOR pathway in development, with 60% of them being used in clinical trials [Li and Wang, ]. Potential problems may include toxic side effects and drug resistance.…”

Clemastine Fumarate Protects Against Myocardial Ischemia Reperfusion Injury by Activating the TLR4/PI3K/Akt Signaling Pathway

“…Our previous study also confirmed that the protective effect of Acanthopanax senticosus and pioglitazone on ischemia-reperfusion cardiomyocytes was related to the PI3K/Akt signaling pathway. However, studies on the PI3K/ Akt pathway has not achieved satisfactory results when applied in clinical trials (Li and Wang, 2014), and possible prevention measures based on the PI3K/Akt pathway mechanism have not yet been studied. Previous studies have found that toll-like receptor 4 (TLR4) is an upstream factor of the PI3K/Akt signaling pathway (Ha et al, 2011).…”

Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas

“…Data about elevated mTORC1-activation in numerous solid tumours and lymphomas are increasing. Our experimental and in vivo xenograft results suggest that the addition of rapalogues to treatment protocols could be beneficial not only in mantle cell lymphomas (MCLs) but also in other lymphomas with high mTORC1 activity -such as Hodgkin lymphomas, non-germinal center type diffuse large B-cell lymphomas and acute lymphoblastic leukemias [24,[37][38][39][40].…”

“…(72 h treatment; co: control; TGF-b1: TGF; Rap: rapamycin; oka: okadaic acid; no inh: without PP2A inhibitor treatment; apoptosis was detected by flow cytometry.). other tumours by increasing or restoring sensitivity to currently available treatment modalities [32,[37][38][39] and to endogenous regulators such as TGF-b1. However, the complex in vivo effects of mTOR inhibition, the availability of endogenous negative regulators (including TGF-b1) and the net effect of these factors need to be clarified in further studies.…”