MODULATION OF THE ANTI-PROLIFERATIVE EFFECT OF OCTREOTIDE IN SOMATOTROPH TUMORS. PARTICIPATION OF FGFR4 AND SHP2

GARCÍA BARBERÁ F.; SOSA L.; PICECH F.; DE BATISTA J; CECENARRO L.; MUKDSI, J; PETITI J. P.

Mar del Plata

Congreso; Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2022

Octreotide (OCT), somatostatin analog that binds with high affinity to receptor SSTR2, is widely used to inhibit GH secretion and cell proliferation in GH-secreting tumors. It has been reported that the phosphatase SHP2 is a key mediator in the signal triggered by SSTR2 and FGFR4, but its role in pituitary tumors is still unknown. The objective was to analyze whether the anti-proliferative effect of OCT is modulated by SHP2 and FGFR4. We determined the protein expression of SHP2 and FGFR4 in 40 PitNETs (12 GH-,3 PRL-, 6 ACTH-secreting and 19 non-functioning tumors) and in human silent GH tumors developed in nude mice treated with OCT for 11d by IHC or/and WB. GH3 cells were treated with OCT, SHP2 inhibitor SHP099 (15 µM), and FGFR4 inhibitors Blu99931 or Roblitibin (100 nM). Protein levels of STAT3 and AKT were determined by WB. Localization of pSTAT3 and FGFR4 were analyzed by IF and cell viability by MTT assay. Statics: ANOVA (Fisher) or t-test. We observed a significant expression of SHP2 in GH-tumors associated with high ki67%, without any differences in FGFR4 levels. The in vivo assays showed that the anti-proliferative effect of OCT was associated with a decrease of SHP2 expression and increase in FGFR4 and pERK1/2. In GH3 cells, the treatment with SHP099 decreased significantly the cell viability, increasing STAT3 phosphorylation and nuclear translocation. Both FGFR4 inhibitors reduced the cell viability and pSTAT3 levels, and the OCT effect was potentiated in presence of Blu99931. Our results suggest that OCT anti-proliferative effects triggered by SSTR2 may be mediated by SHP2 in functioning and non-functioning pituitary adenomas. These results indicate that the inhibition of SHP2 and FGFR4 are important for strengthening the antiproliferative effects of OCT, being STAT3 a molecular hub integrating the receptors signaling pathways.