mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Everolimus is a potential medical therapy for pancreatic neuroendocrine tumors (P-NET).
• Predicting therapeutic response to Everolimus in P-NET remains a clinical challenge.
• The PI3K/AKT/mTOR pathway is implicated in cancer cell proliferation and survival.

Purpose of the Study:

• To identify predictive markers for Everolimus response in pancreatic neuroendocrine tumors.
• To investigate the role of the PI3K/AKT/mTOR pathway in Everolimus resistance.

Main Methods:

• Primary cultures of 6 Everolimus-sensitive (P-NET-R) and 14 Everolimus-resistant (P-NET-NR) pancreatic neuroendocrine tumors were established.
• Cell viability and apoptosis assays were performed to assess Everolimus efficacy.
• Immunohistochemistry (IHC) for phosphorylated AKT (p-AKT) was conducted on patient tissues.

Main Results:

• Everolimus reduced cell viability and induced apoptosis in P-NET-R cultures, blocking IGF1 effects.
• P-NET-NR cultures were resistant to Everolimus and IGF1, suggesting PI3K/AKT/mTOR pathway involvement.
• In vitro Everolimus response correlated with an active AKT/mTOR pathway and clinical aggressiveness.
• A patient sensitive in vitro was also sensitive in vivo, showing positive p-AKT IHC.
• A resistant patient showed negative p-AKT IHC and in vitro resistance.

Conclusions:

• Primary P-NET cultures serve as a reliable model for testing Everolimus efficacy.
• p-AKT immunohistochemistry may help identify P-NET patients likely to benefit from Everolimus.
• Further prospective multicenter studies are warranted to validate these findings.