NEW THERAPEUTIC TARGETS IN SOMATOTROPINOMAS: SHP2 AND FGFR4

Congreso; Congreso SAIC 2023; 2023

Octreotide (OCT), a somatostatin analog, binds SSTR2 to inhibit proliferation via SHP1, SHP2, and PTPꞃ in somatotropinomas. In this tumor, the FGFR4 receptor has been described as a prognostic and therapeutic biomarker. In addition, recent studies suggest that SHP2 is a key mediator in the signaling of SSTR2 and FGFR4; however, its role in tumor growth and therapeutic response in somatotopinomas is still unknown. Our aim was to assess whether SHP2 and FGFR4 modulate the OCT effect.SHP2 and FGFR4 expression was evaluated in 41 human samples: 36 PitNETs (GHx9, ACTHx8, PRLx2, NFx16), 6 controls, and PDX NUDE mice tumors post-11-day OCT treatment (IHQ, WB).GH3 and patient-derived cells were treated with OCT, SHP2 (SHP099,15 µM) or FGFR4 inhibitors (Blu99931 and Roblitinib, 50-100 nM). pSTAT3-Tyr705, pERK1/2, pAKT were analyzed by WB and IF. Viability (MTT) and proliferation (BrdU) were examined. Python analyzed RNA-seq (GSE209903). Stats: Kruskal-Wallis, ANOVA, t-test, Chi2, Pearson. The bioinformatic analysis showed that FGFR4 is less expressed in GH tumors compared to ACTH and non-functioning PitNETs, while the level of SHP2 was similar in all PitNET phenotypes. Gene expression data showed a negative correlation between SHP2 and FGFR4, but positive with STAT3, particularly in GH tumors. In our cohort, the somatotropinoma expressed more SHP2 compared to non-tumor tissue, without clinical factor correlations. Patients pre-treated with OCT showed highest FGFR4 H-score than non-treated (p<0.01). In PDX (somatotropinoma) mice OCT treatment for 11d blocked tumor growth, decreased SHP2 and increased FGFR4 expression(p<0.001). In vitro, SHP2 inhibitor decreased the proliferation of GH-secreting cells, effect associated with a reductions of pSTAT3 levels, and Blu99931 enhanced the anti-proliferative effect of OCT (p<0.001). In addition, OCT induced translocation of SHP2 to the plasma membrane and pSTAT3 to the nucleus. The results suggest the therapeutic potential of SHP2 and the use of FGFR4 inhibitors for the optimization of OCT treatment, especially in patients with high expression of this receptor or with somatostatin analog resistance.