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

GARCIA-BARBERA, F; SOSA LDV; PICECH, F; DE BATISTA J; CECENARO L; MUKDSI, J. H.; PETITI J P

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 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 39 PitNETs (12 GH-,3 PRL-, 7 ACTH-secreting and 17 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 (100 nM), SHP2 inhibitor SHP099 (15 µM), and FGFR4 inhibitors Blu99931 or Roblitinib (50-100 nM). Protein levels of pSTAT3 and p-ERK 1/2 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. In GH- tumors we observed a higher SHP2 expression in associated with high ki67% without remarkable FGFR4 expression in comparison to other tumors subtypes. The in vivo assays showed that the anti-proliferative effect of OCT was associated with a decrease of SHP2 expression and increase of FGFR4 and pERK1/In GH3 cells, the treatment with SHP099 decreased the cell viability, increasing STAT3 phosphorylation and nuclear translocation. Both FGFR4 inhibitors reduced significantly the cell viability and pSTAT3 levels, and the OCT effect was potentiated in presence of Blu99931. These results indicate that SHP2 and FGFR4 inhibition are important for strengthening the antiproliferative effects of OCT, being STAT3 a molecular hub integrating the receptors signaling pathways, possibly being part of a counterbalance mechanisms.