The Role of Splicing Machinery as a Promising Potential Therapeutic Target for Pituitary Neuroendocrine Tumors (PitNETs).

Pituitary neuroendocrine tumors (PitNETs) represent one of the most common intracranial lesions. The pharmacological approach to PitNETs is mainly based on the use of somatostatin (SS) receptor ligands (SRLs) and dopamine agonists (DAs), although resistance or poor efficacy occurs in a percentage of patients. SS receptors (SSTs) and dopamine receptor type 2 (DRD2) represent the principal targets of SRLs and DAs, respectively, in PitNET therapy. Over the years, SSTs and DRD2-related activated pathways have been characterized. Different factors that might play a role in affecting intracellular signaling transduction have been studied, including splicing machinery and its related factors. A severe dysregulation of splicing machinery components in all PitNET subtypes compared to normal pituitary was observed, and possible alterations that might underlie pharmacological resistance or intracellular pathway alterations were investigated. The detection of these alterations presented the opportunity to investigate small molecules that regulate splicing components as an alternative approach for PitNETs treatment. A systematic literature search was conducted in the PubMed database and supplemented by screening the references of the identified articles. A narrative synthesis of the research findings was provided, including relevant studies from 2015 up to date. It aimed to summarize the emerging role of splicing machinery, focusing on different splicing factors shown to be altered in different PitNET subtypes that might affect responsiveness to pharmacological treatment. Different ways to target splicing machinery and its mechanism of action have been described, with the goal of developing novel therapies for PitNETs.