US EPA

7432717 

Journal Article 

PI3K/Akt/mTOR/PTEN and ERK/MAPK Pathways 

Lotan, TL; , 

2018 

367-379 

10.1007/978-3-319-64096-9_21 

http://link.springer.com/10.1007/978-3-319-64096-9_21
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Aberrant activation of oncogenic intracellular signaling pathways in prostate cancer holds enormous promise as a potential therapeutic target. Of these signaling circuits, PI3K/AKT/mTOR signaling is one of the most important in the disease, and numerous compounds targeting this pathway are currently being tested in clinical trials or preclinical models of prostatic tumorigenesis. In the vast majority of tumors, PTEN loss by genomic deletion is one of the earliest and most critical events leading to activation of downstream PI3K/AKT/mTOR signaling. While amplifications of PI3K component genes also occur, activating mutations of PI3K or downstream AKT/mTOR signaling are relatively rare compared to their common occurrence in other solid tumor types. Though activation of RAS/RAF/MEK/ERK signaling comprises another important oncogenic circuit in prostate cancer, the molecular mechanisms responsible for this remain unclear. Activating mutations in MAPK constituents and gene fusions leading to activation rarely occur but may be targetable in rare cases. Ultimately, realizing the promise of precision medicine approaches for targeting these critical signaling pathways will hinge on the development and extensive validation of molecular pathology assays to assess pathway status.