Resistance to cabergoline treatment in human primary non-functioning pituitary tumour cells

F. Begalli*^a (Dr), T. Komagata^b (Mr), O. Suleyman^a (Ms), K. Magid^a (Dr), T. Rice^a (Dr), D. Collier^a (Dr), N. Dorward^c (Dr), J. Grieve^c (Dr), N. Mendoza^d (Dr), N. Ramesh^d (Dr), A. Kolias^c (Dr), D. Khan^c (Dr), HJ. Marcus^c (Dr), J. Botta^a (Dr), PJ. Mccormick^a (Dr), K. Shinozaki^b (Dr), M. Korbonits^a (Prof)

^a William Harvey Research Institute, Queen Mary University of London, London, UNITED KINGDOM ; ^b Ono Pharmaceutical Co., Ltd, Osaka, JAPAN ; ^c UCL Queen Square Institute of Neurology, London, UNITED KINGDOM ; ^d Charing Cross Hospital, London, UNITED KINGDOM

* f.begalli@qmul.ac.uk

Introduction: Clinically non-functioning pituitary adenomas (NFPAs) represent the second most common subtype of pituitary tumours. NFPAs are usually benign tumours, most commonly arising from gonadotroph lineage with no clinical evidence of hormonal hypersecretion. As result of lack of hormonal hyper-secretion, the diagnosis of NFPAs is made most often when the patient presents with mass effects.

NFPAs remain the only subtype of pituitary adenomas with surgery as the only treatment option. However, complete resection is achieved only in about 66% of the cases, and 20% of gross total resected tumours recur after 10 years. Dopamine receptor type 2 (DRD2) and somatostatin receptor (SST) expression have been demonstrated in NFPAs, prompting the investigation of dopamine agonists and somatostatin analogues as potential treatment strategies.

Material and Methods: Patients’ samples, NFPAs n=33 (gonadotrophinoma), prolactinomas n=10 (clinically partially resistant), somatotrophinoma n=8, normal pituitaries n=7 (autopsy).

Results: We assessed DRD2 expression levels via qPCR in a large cohort of NFPAs (n=33) and in few prolactinomas (n=10). D2DR has two different isoforms, long (D2RL) and short (D2RS), in cabergoline-sensitive prolactinomas D2RS is the predominant isoform. NFPAs shown 20-fold and 10-fold decrease expression of D2RS and D2RL compared to prolactinomas, respectively. Additionally, in NFPAs we observed a significant decrease of cAMP production after cabergoline treatment (45%; p<0.0001); however, one-week of cabergoline, a D2DR agonist, treatment did not reduce viability (4%; p<0.0002), and neither we observed reduction in chromogranin A secretion upon cabergoline treatment.

Like D2DR, we have observed downregulation of Ga_i2 expression in NFPAs, the G-protein involved in D2RS pathway (3-fold, p<0.004). Furthermore, no expression difference was observed in b-arrestin2, involved in D2RS signalling and in cabergoline sensitiveness in prolactinomas.

Discussion: Our data suggest that NFPAs will respond differently to cabergoline treatment due to their distinct expression of D2DR isoforms and Ga_i2. The difference in D2R isoform expression could translate to distinct G-protein activation, ultimately leading to the contrasting viability results after cabergoline treatment. Furthermore, similar expression levels of b-arrestin2 between NFPAs and resistant prolactinomas could help identifying resistance to cabergoline. Taken together, these data will help inform future treatment strategies for patients with NFPAs.

The author has declared no conflict of interest.