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Predictive value of metabolic state on PanNET response to mTOR inhibitors
Jérôme Cros1,2,3, Margot Bucau1,3, Matthieu Tihy1,3
1Inserm U1149-CRI, Beaujon Hospital, Clichy, France.
Endocrine-Related Cancer
|September 16, 2025
Summary
mTOR inhibitors show promise for pancreatic neuroendocrine tumors (PanNET), but resistance is common. A pseudohypoxic/glycolytic metabolic profile predicts resistance to these drugs, offering potential biomarkers for treatment selection.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- mTOR inhibitors like everolimus are used for pancreatic neuroendocrine tumors (PanNET) but have side effects and lack predictive biomarkers.
- Understanding resistance mechanisms is crucial for improving PanNET treatment efficacy.
Purpose of the Study:
- To identify molecular pathways associated with resistance to mTOR inhibitors in PanNET.
- To evaluate the predictive value of identified biomarkers in patients treated with everolimus.
Main Methods:
- Precision-cut PanNET slices were cultured with mTOR inhibitors (everolimus, BEZ235) and analyzed for apoptosis and pathway markers.
- Transcriptomic analysis compared sensitive and resistant tumors.
- Candidate pathways were validated by immunohistochemistry and assessed in patient cohorts.
Main Results:
- mTOR inhibition induced apoptosis in sensitive PanNET slices.
- Sensitive tumors showed mitochondrial metabolism, while resistant tumors exhibited a pseudohypoxic/glycolytic profile (high CAIX, GLUT1, ATP5O, mtTFA).
- High CAIX and LDHA expression correlated with shorter progression-free survival in patients receiving everolimus.
Conclusions:
- Tissue culture is effective for assessing PanNET drug response.
- A pseudohypoxic/glycolytic profile predicts resistance to mTOR inhibitors in PanNET.
- CAIX and LDHA are potential biomarkers for predicting response to everolimus in PanNET.
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