New therapeutic targets in somatotropinomas: SHP2 and FGFR4

Abstract

Octreotide (OCT), a somatostatin analog, binds to the SSTR2 receptor, acting as an anti-secretory for GH and exhibiting anti-proliferative effects in somatotropinomas. In this type of tumors, the FGFR4 receptor has been described as a prognostic and therapeutic biomarker. Furthermore, studies suggest that SHP2 is a key mediator in SSTR2 and FGFR4 signaling. However, its role in tumor growth and therapeutic response in pituitary adenomas remains unknown. The objective was to evaluate whether SHP2 and FGFR4 modulate the anti-proliferative effect of OCT.

Protein expression of SHP2 and FGFR4 was assessed in 38 PitNETs (GHx9, ACTHx8, PRLx2, NFx16, normalx6) and in OCT-treated NUDE mice patient-derived tumors for 11 days using IHC and/or WB. GH3 cells and patient-derived cells were treated with OCT, the SHP2 inhibitor SHP099 (15 µM), and FGFR4 inhibitors Blu99931 or Roblitinib (50-100 nM). pSTAT3-Tyr705, pERK1/2, pAKT were analyzed by WB and IF, along with viability (MTT) and proliferation (BrdU). Bioinformatic analysis of RNA-seq GSE209903 was performed by Python. Statistical methods included ANOVA, t-test, Chi2, Pearson. RePIS No. 3390. Protocol approved by CICUAL-FCM-UNC.

Bioinformatic analysis revealed that FGFR4 is less expressed in GH tumors compared to ACTH and NF tumors, while SHP2 is uniformly expressed (p<0.0001). In our cohort, somatotropinomas exhibited higher SHP2 levels than normal tissue, without direct correlation with clinical factors. Patients treated with OCT prior to surgery showed higher FGFR4 expression than untreated patients (p<0.01). In OCT-treated mice, SHP2 levels decreased and FGFR4 levels increased (p<0.001). OCT induced SHP2 translocation to the plasma membrane and pSTAT3 translocation to the nucleus, effects that could be linked to increased FGFR4 expression after OCT treatment. In vitro, SHP2 and FGFR4 inhibitors decreased cell viability and proliferation (<0.001). SHP099 decreased STAT3-tyr705 phosphorylation levels. The antiproliferative effect of OCT was enhanced in the presence of the FGFR4 inhibitor (Blu99931).

The results suggest the therapeutic potential of SHP2 and the use of FGFR4 inhibitors to optimize OCT treatment, especially in patients with high receptor expression or therapeutic resistance.