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.
Highlights
Dopamine agonists (DAs) are chemical compounds that, by directly binding to the dopamine receptors (DRs), induce biological actions resembling that of endogenous dopamine [1]
The main localization of D2DR is on normal and tumoral animal and human lactotroph pituitary cells [2, 4, 5], DAs represent the treatment of choice for PRL-secreting pituitary neuroendocrine tumors (PitNET), Dopamine Agonists Resistance in PitNETs for whose management, unlike other PitNET, the consensus guidelines have recommended the medical therapy as first-line treatment of choice rather than surgery [6]
A lower messenger expression of D2 short (D2S) and D2S/D2 long (D2L) ratio has been confirmed in the DAs resistant pituitary tumors [12, 27, 28, 54, 56, 59], in a Japanese study the resistance to DAs in prolactinomas has been surprisingly correlated to a reduced messenger expression of D2L receptor subtype [57]
Summary
Dopamine agonists (DAs) are chemical compounds that, by directly binding to the dopamine receptors (DRs), induce biological actions resembling that of endogenous dopamine [1]. DAs, mainly CAB, are indicated as monotherapy in patients with GH-secreting PitNET with mild disease [13], defined as mild signs and symptoms of GH excess and modest elevation in serum IGF-I levels (lower than 2 times the upper limit of normal) [14] In such patients, CAB administration has resulted in the achievement of biochemical control in approximately one-third of patients [15]. In CD, DAs are listed among the pituitary-directed drugs for patients with ACTH-secreting PitNET, including those who have experienced a noncurative surgery or a postoperative recurrence and are not candidates for additional pituitary surgery [18] In such patients, the use of CAB has resulted in the achievement of biochemical control in up to 40% of cases [19]. D2DR activation of ROCK/LIMK pathway determinates the inactivation of the protein cofilin, an actin-binding protein that regulates filament dynamics, with a consequent loss of its ability to bind the actin and, promoting cell migration [44]
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