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Updated: May 24, 2025
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
SHP2 inhibition reduces somatotroph tumor growth in a pre-clinical model
Facundo García Barberá1,2, Florencia Picech3, Laura Cecenarro4,1,2
1Instituto de Investigaciones en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina.
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.
Insights
Somatotroph tumors show increased SHP2 expression. Inhibiting SHP2 (a phosphatase) reduced tumor growth and STAT3 phosphorylation, identifying it as a potential therapeutic target for these tumors.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Over 50% of patients with somatotroph tumors show poor response to octreotide (OCT).
- OCT stimulates SSTR2, activating anti-proliferative pathways via the phosphatase SHP2.
- SHP2's interaction with STAT3, particularly their subcellular localization, is key to its mechanism.
Purpose of the Study:
- To investigate SHP2 expression in somatotroph tumors.
- To determine SHP2's role in tumor cell proliferation.
- To analyze SHP2's effects on STAT3 phosphorylation and subcellular localization.
Main Methods:
- Bioinformatic analysis, IHC, and WB for SHP2 expression in PitNETs.
- In vitro and in vivo studies using GH3 cells, patient-derived tumor cells, and a PDX model to assess SHP099's effect on proliferation.
- WB, IF, and MET to analyze SHP2's impact on STAT3, AKT, ERK1/2 activation and SHP2/STAT3 localization.
Main Results:
- SHP2 expression was elevated in somatotroph tumors and correlated with invasiveness.
- OCT's anti-proliferative effects and adaptation were linked to SSTR2 and SHP2 expression.
- SHP099 treatment reduced cell proliferation, tumor growth, and phosphorylation of STAT3-Tyr705, AKT, and ERK1/2.
Conclusions:
- SHP2 is upregulated in somatotroph tumors.
- Pharmacological inhibition of SHP2 reduced in vitro and in vivo tumor cell proliferation.
- SHP2 represents a novel therapeutic target for somatotroph tumors, impacting STAT3 phosphorylation.
