Heterogeneity of Phosphatidylinositol-3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin Activation in Cancer: Is PI3K Isoform Specificity Important?

摘要

Introduction One of the most common events in human cancer is hyperactivation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, generally described as a consequence of genetic alterations of pathway members. The core components of the pathway are depicted in Figure 1 A. There are four members of the class I PI3Ks, which act upstream of this pathway, performing the conversion of phosphatidylinositol-4,5-bisphosphate (PIP_(2)) into phosphatidylinositol-3,4,5-trisphosphate (PIP_(3)). This lipid produced in the inner leaflet of the plasma membrane controls a range of cellular actions including cell growth, migration, metabolism, survival and proliferation. Class I PI3K activity in vertebrates regulates both physiological and pathological processes ( 1 ). Figure 1 Heterogeneity of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) activation in cancer: global and comprehensive mapping by a multiscale integrated approach. (A) Representation of PI3K/AKT/mTOR canonic members. Most omics results use data obtained under treatment with pan-PI3K inhibitors which still display relative isoform specificity, or with PI3Kα-selective inhibitors associated with genetic alterations. Usually, only the expression of PIK3CA and PIK3CB is studied. Production of PIP_(3)at the plasma membrane is, however, performed by four enzymes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. They are composed of a regulatory subunit (p85 or p101/p87) and a catalytic subunit (p110α, p110β, p110δ, or p110γ). (B) This schematic summarizes the bioinformatic meta-analysis performed in the study by Zhang et al. ( 2 ) using two PI3K/AKT/mTOR transcriptional signatures of Creighton et al. and Garnett et al. ( 3 , 4 ). (C) Representation of the molecular alterations found in cancer patients with high PI3K/AKT score. Molecular alterations in patients with reverse-phase protein array (RPPA) score values ≥0.5 are shown. These RPPA scores were normalized to SDs from the median across all cancers. Phosphatidylinositol-3-kinase activity has been implicated in a variety of different cancers, hence this class of enzymes is a prime drug target for anticancer therapies ( 5 ). However, initial phase I/II clinical trials of small molecule PI3K inhibitors show that the predictive markers of efficiency of these drugs need to be improved. The presence of PIK3CA mutation in the primary tumor alone is not a sufficient predictive marker of efficiency ( 6 , 7 ). Signal-targeted therapy would benefit from the identification of patients more likely to respond. A Recent Multiscale Omics Approach Mapped PI3K/AKT/mTOR Activation in Cancer Zhang et al. analyzed in an unbiased fashion both known molecular mechanisms by which the PI3K/AKT/mTOR pathway is upregulated in human cancers, as well as other possibly unrelated genetic alterations ( 2 ). They examined The Cancer Genome Atlas open access omics data (including genomic mutations by whole-genome sequencing, gene copy number by single-nucleotide polymorphism array, or RNA expression by whole-exome sequencing) across 11,219 human cancers representing 32 distinct major types. The authors also used reverse-phase protein array (RPPA) analysis to assess the level of expression of 166 total proteins and 56 phosphorylated proteins (Figure 1 B). Phosphoproteome-based PI3K/AKT and mTOR activity signatures (p-AKT_(S473/T308), p-GSK3_(S9), p-PRAS40_(T246), p-TSC2_(T1462)and p-mTOR_(S2448), p-RICTOR_(T1135), p-4EBP1_(S65/T34/T46/T70), p-S6K_(T389), p-S6_(S235/S236/S240/S244), respectively) by RPPA analysis were found to be correlated. Transcriptomics analysis found that the levels of expression of a selected list of members of the PI3K/AKT pathways were not correlated with the activation of PI3K or mTOR signaling nodes by RPPA. However, the authors confirmed a correlation between the transcriptional expression and alterations in the copy number of the so-called core genes. All mutated residues of members of the PI3K/AKT/mTOR pathway resulted in the expected increase in activity of the PI3K/AKT/mTOR pathway. Therefore, modifications to DNA, mRNA expression, and phosphoprotein levels were found to be functionally relevant in the hyperactivation of the PI3K pathway associated with cancers. Not all Cases of Increased PI3K/AKT/mTOR Pathway Activity Can be Explained by the Canonic Genetic Alterations Associated with PI3K Signaling In most scenarios, increased AKT activity can be explained by genetic or genomic alterations to members of the PI3K/AKT/mTOR pathway; however, this is not the case for all instances of AKT hyperactivation (Figure 1 C). In 764 of 7,099 tumors, including mostly lower grade glioma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, and kidney renal clear cell carcinoma, the level of phospho-AKT was increased without any of the genetic or genomic alterations described as being functionally coupled to this pathway. In addition, upregulation of mTOR