Neuro-oncology · 2025
SHP2 inhibition reduces somatotroph tumor growth in a pre-clinical model.
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García Barberá Facundo, Picech Florencia, Cecenarro Laura, Mezger Gilda Florencia, Faure Erica, Zlocowski Natacha, Calafat Patricia, De Battista Juan Carlos, Mukdsi Jorge Humberto, Sosa Liliana Del Valle, Petiti Juan Pablo
Аннотация
BACKGROUND: In somatotroph tumors, over 50% of patients do not respond satisfactorily to the octreotide (OCT) treatment. Stimulation of SSTR2 with OCT triggers anti-proliferative signaling pathways mediated by the phosphatase SHP2. This phosphatase can exercise its functions through the STAT3, with the SHP2/STAT3 subcellular localization being crucial for understanding its mechanisms of action. We investigated the expression of SHP2 in somatotrophs tumors, the role of SHP2 on cell proliferation, its effects on STAT3 phosphorylation, and SHP2/STAT3 subcellular localization, using in vitro and a pre-clinical model.
METHODS: Protein and mRNA expression of SHP2 were evaluated in PitNETs by bioinformatic analysis, IHC and WB. The effect of SHP099 on cell proliferation was determined in GH3 cells, patient derived tumor cells and in a PDX model. The effect of SHP2 on STAT3, AKT, and ERK1/2 activation was analyzed by WB, and SHP2/STAT3 subcellular localization was evaluated by IF and MET.
RESULTS: We observed increased SHP2 expression in somatotroph tumors being associated with invasiveness. The anti-proliferative effect of OCT and its adaptation after long-term exposure may be driven by the expression of SSTR2 and SHP2. The treatment with SHP099 decreased cell proliferation, tumor volume growth, necrosis as well as the phosphorylation of STAT3-Tyr705, AKT, and ERK1/2.
CONCLUSION: We have demonstrated that SHP2 is more expressed in somatotroph tumors, with its pharmacological inhibition resulting in a reduction of both in vitro and in vivo cell proliferation via STAT3 phosphorylation, making this phosphatase a novel clinical target with promising effects on somatotroph tumors.
METHODS: Protein and mRNA expression of SHP2 were evaluated in PitNETs by bioinformatic analysis, IHC and WB. The effect of SHP099 on cell proliferation was determined in GH3 cells, patient derived tumor cells and in a PDX model. The effect of SHP2 on STAT3, AKT, and ERK1/2 activation was analyzed by WB, and SHP2/STAT3 subcellular localization was evaluated by IF and MET.
RESULTS: We observed increased SHP2 expression in somatotroph tumors being associated with invasiveness. The anti-proliferative effect of OCT and its adaptation after long-term exposure may be driven by the expression of SSTR2 and SHP2. The treatment with SHP099 decreased cell proliferation, tumor volume growth, necrosis as well as the phosphorylation of STAT3-Tyr705, AKT, and ERK1/2.
CONCLUSION: We have demonstrated that SHP2 is more expressed in somatotroph tumors, with its pharmacological inhibition resulting in a reduction of both in vitro and in vivo cell proliferation via STAT3 phosphorylation, making this phosphatase a novel clinical target with promising effects on somatotroph tumors.