What happens in the PI3K–AKT pathway?

The use of sequencing has shown that in 20-40% of primary tumors and 49% CRPCs genetic alterations in the PI3K-AKT pathway are present. The genomic alterations impact tumorigenesis through the activation of target genes, resulting in cell growth, the progression of cell cycle and proliferation. It has been shown that hyperactivity of the PI3K-AKT pathway seems to be most commonly as a result of PTEN activation. However, other alterations such as those in PIK3CA, PIK3CB, PIK3R1, PIK3R3, and AKT1 also play a role in PI3K-AKT hyperactivity. Of note seems to be the existence of a negative feedback loop existing between AR-signalling and the PI3K-AKT pathway, which has been shown in vitro studies. This has shown that direct inhibition of either result in the hyperactivity of the other, leading to suggestions that inhibition of both pathways is required for achieving desired clinical responses.

As mentioned, it is the genomic inactivation of PTEN, through its activity as a negative regulator of the PI3K-AKT pathway which serves as the most common alteration in the pathway, found to occur in around 40% of CRPCs. Most common disruptions of PTEN arise as a result of genomic deletions. However, disruptions can also arise as a result of mutations or structural arrangements.

The use of analysis using developed immunohistochemistry (IHC) assay in concordance with previously published fluorescence in situ hybridization studies (FISH) has shown that loss of PTEN expression on IHC correlates with poor prognosis in patients, in particular cases that are ERG-fusion-negative. Loss of PTEN expression has also been associated with higher Gleason scores (GS) and the upgrading of tumors in prostatectomy specimens of GS 6 in needle biopsies.