Abstract
In this review, we will first briefly describe the diverse molecular mechanisms associated with PTEN loss of function in cancer. We will then proceed to discuss the molecular mechanisms linking PTEN loss to PI3K activation and demonstrate how these mechanisms suggest possible therapeutic approaches for patients with PTEN-null tumors.
Highlights
A targeted, massively parallel sequencing project that assessed the frequency of mutations in 47 genes, including PIK3CA, phosphatase and tensin homolog (PTEN), and AKT1, in 19,784 consecutive diverse solid tumors from 60 countries supported previous studies that aberrations in the phosphoinositide 3-kinase (PI3K) pathway are frequently observed in a broad range of human tumors [23]
Cizmecioglu et al further demonstrated that p110β-dependent PTEN-null tumor cells critically rely on raft-associated PI3K signaling [159]
The results showed suppressed growth of PTEN-null human cancer cells [164]
Summary
Hyperactivation of the PI3K pathway is frequently found in many types of human cancer. In the case of tumors driven by activated RTKs, the deletion of p110α is sufficient to block tumor initiation, while deleting p110β can increase tumor size [17] This appears to occur in part because both enzymes compete for activation motifs on the RTKs, and p110α has a much higher specific activity than p110β. This high specific activity may explain why the PIK3CA gene is a better mutational target in human tumors, though other mechanisms may be relevant. A targeted, massively parallel sequencing project that assessed the frequency of mutations in 47 genes, including PIK3CA, PTEN, and AKT1, in 19,784 consecutive diverse solid tumors from 60 countries supported previous studies that aberrations in the PI3K pathway are frequently observed in a broad range of human tumors [23]. Breast, prostate, and lung cancers, the study found that anal, liver, and colorectal cancers contained mutations in PI3K pathway genes with high frequency
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