Endocrine Abstracts

Prolactinomas are the most frequent pituitary tumors, and dopamine agonists (DA) are their first-choice treatment, since they normalize PRL levels and reduce tumor size in the majority of patients, by binding to dopamine receptor type 2 (DRD2) on tumoral cells. However, drug resistance occurs in a subset of patients, involving different steps following receptor activation or during the final biological responses. Although resistance to DA has been correlated with a reduced DRD2 expression, or with an altered ratio between the two isoforms of DRD2, the success of the therapy also requires the proper functioning of the machinery of signal transduction and receptor intracellular trafficking. A variety of molecules, including β-arrestins, filamin A (FLNA) and splicing factors might affect the efficacy of therapy. FLNA is a cytoskeleton actin-binding protein crucial for DRD2 expression, membrane localization and signaling. Since FLNA phosphorylation switches FLNA function from a scaffold that allows DRD2 signal transduction to a signal termination protein that hampers all DRD2 antitumoural effects in prolactinoma cells, new possible pharmacological approaches can target FLNA post-translational modification. The scaffold protein β-arrestin 2 is essential for DRD2 inhibitory effects on AKT phosphorylation with a consequent reduction of cell proliferation in prolactinoma cells. This observation not only suggest a potential role of β-arrestin 2 as a biomarker predicting prolactinoma responsiveness to treatment with DA, but also a novel pharmacological strategy based on functionally selective or biased DRD2 agonists that preferentially activate the β-arrestin 2-mediated pathway at the expense of the canonical G-protein-mediated ones. Alternative splicing is a crucial mechanism for gene regulation, generating different functional proteins, and this process can be dysregulated in cancer. In particular, a severe dysregulation of splicing-machinery components in all the pituitary tumor subtypes compared to normal pituitaries has been observed. Somatic mutations in splicing factor3 subunitB1 (SF3B1) were found in about 20% of PRL-secreting pituitary tumors in a single paper, associated with PRL hypersecretion, increased cell proliferation and invasion. These data provide the rationale for investigating new therapeutic strategies based on SF3B1 inhibition, as well as for testing the effects of splicing alterations on DRD2 expression and responsiveness to treatment with DA. Further studies of the complex mechanisms involved in the resistance of prolactinomas to DRD2-targeted therapy could provide the basis for the development of both new prognostic biomarkers that can be used for patient selection and management and novel targets for the pharmacological treatment of these tumors.