Resistance to Dopamine Agonists in Pituitary Tumors: Molecular Mechanisms

Abstract

Pituitary neuroendocrine tumors (PitNET) are commonly benign tumors accounting for 10-25% of intracranial tumors. Prolactin-secreting adenomas represent the most predominant type of all PitNET and for this subtype of tumors, the medical therapy relies on the use of dopamine agonists (DAs). DAs yield an excellent therapeutic response in reducing tumor size and hormonal secretion targeting the dopamine receptor type 2 (D2DR) whose higher expression in prolactin-secreting adenomas compared to other PitNET is now well established. Moreover, although DAs therapy does not represent the first-line therapy for other PitNET, off-label use of DAs is considered in PitNET expressing D2DR. Nevertheless, DAs primary or secondary resistance, occurring in a subset of patients, may involve several molecular mechanisms, presently not fully elucidated. Dopamine receptors (DRs) expression is a prerequisite for a proper DA function in PitNET and several molecular events may negatively modify DR membrane expression, through the DRs down-regulation and intracellular trafficking, and DR signal transduction pathway. The current mini-review will summarise the presently known molecular events that underpin the unsuccessful therapy with DAs.

Keywords: cabergoline; dopamine; dopamine agonist; pituitary tumors; prolactinomas.

Figure 1

Molecular mechanisms underpinning the DAs resistance in PRL- and GH-secreting PitNET. 1) The gene variant NcoI T+ of the synonymous polymorphism NcoI, consisting in a cytosine to thymine (NcoI C/T) transition at position 957, leads to a decreased D2DR mRNA stability and synthesis through a putative alteration in the receptor mRNA folding, conferring resistance to the antitumoral action of CAB in PRL-secreting PitNET; 2) Estrogens may affect the D2S/D2L ratio tumors, increasing the expression of D2L and therefore affecting the efficacy of DAs treatment in PRL-secreting PitNET; 3) D2DR in PRL-secreting PitNET cell model and primary cultures of nonfunctioning PitNET triggers the β-arrestin 2-mediated PKB dephosphorylation inducing antiproliferative effect and the lack of β-arrestin 2 induces DAs resistance in nonfunctioning PitNET; 4) FLNA is involved in the regulation of D2DR membrane expression and signalling. Indeed, FLNA anchorage and expression of D2DR on the plasma membrane, by controlling D2DR fate towards recycling processes or degradation in PRL- and GH-secreting PitNET; 5) D2DR activates ROCK/LIMK pathway with consequent inactivation of the protein cofilin resulting in a loss of its ability to bind the actin and, thus, promoting cell migration and invasion; 6) miR-93-5p targets Smad7, a negative regulator of TGF-β1/Smad signalling, sustaining the TGF-β1-induced fibrosis in PRL-secreting PitNET. Alongside, miR-93-5p down-regulates p21 inducing cell-cycle progression and losing the control of ROCK/LIMK pathway, and down-regulates ATG7, decreasing the autophagic cell death induced by CAB in PRL- and GH-secreting PitNET; 7) the reduced expression of miR-145-5p stimulates the TPT1 protein resulting in decreased DNA repair, increased cell migration and invasion and reduced apoptosis and autophagy. D2DR, dopamine receptor type 2; PKB, protein-kinase B; FLNA, filamin A; ROCK, Rho-associated protein kinase; LIMK, LIM kinase; ATG7, Autophagy Related 7 protein; TPT1, translationally controlled tumor protein. Created with BioRender.com.