Activation of the PI3K/mTOR/AKT Pathway and Survival in Solid Tumors: Systematic Review and Meta-Analysis

Abstract

BackgroundAberrations in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components of this pathway. However the prognostic value of these aberrations is unclear.MethodsPubMed was searched for studies evaluating the association between activation of the PI3K/mTOR/AKT pathway (defined as PI3K mutation [PIK3CA], lack of phosphatase and tensin homolog [PTEN] expression by immunohistochemistry or western-blot or increased expression/activation of downstream components of the pathway by immunohistochemistry) with overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (OR) for death at 5 years. Data were pooled using the Mantel-Haenszel random-effect model.ResultsAnalysis included 17 studies. Activation of the PI3K/mTOR/AKT pathway was associated with significantly worse 5-year survival (OR:2.12, 95% confidence intervals 1.42–3.16, p<0.001). Loss of PTEN expression and increased expression/activation of downstream components were associated with worse survival. No association between PIK3CA mutations and survival was observed. Differences between methods for assessing activation of the PI3K/mTOR/AKT pathway were statistically significant (p = 0.04). There was no difference in the effect of up-regulation of the pathway on survival between different cancer sites (p = 0.13).ConclusionActivation of the PI3K/AKT/mTOR pathway, especially if measured by loss of PTEN expression or increased expression/activation of downstream components is associated with poor survival. PIK3CA mutational status is not associated with adverse outcome, challenging its value as a biomarker of patient outcome or as a stratification factor for patients treated with agents acting on the PI3K/AKT/mTOR pathway.

Effects of PHA-665752 and vemurafenib combination treatment on in�vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations

“…Activation of the PI3K/AKT and MEK/ERK pathways is common in different types of cancer (20)(21)(22)(23) and, in solid tumors, it is often associated with poor prognosis (24). AKT and ERK play crucial roles in cell proliferation, metastasis, angiogenesis, and drug response.…”

Chorein Sensitive Dopamine Release from Pheochromocytoma (PC12) Cells

“…PI3K signaling is further known to confer survival of a wide variety of cells including cancer cells [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55] and neurons [56,57,58,59]. Chorein is particularly important for function and viability of neurons and skeletal muscle cells [6,11].…”

FANCI is a negative regulator of Akt activation

“…[1][2][3] PI3K and Akt are two of the most commonly dysregulated oncogenes, and PTEN, a negative regulator of the pathway, is among the most frequently mutated tumor suppressors. 4 This pathway controls most aspects of cancer progression including cell proliferation, survival, metabolism, motility, and genomic instability.…”