Combined Targeting of Pathogenetic Mechanisms in Pancreatic Neuroendocrine Tumors Elicits Synergistic Antitumor...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Pancreatic neuroendocrine neoplasms (PanNENs) are the second most common pancreatic malignancy.
• Curative treatment is limited to localized disease; advanced/metastatic cases have few, unpredictable targeted therapies.
• Understanding PanNEN tumorigenesis is crucial for developing effective treatments.

Purpose of the Study:

• To evaluate buparlisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor) as single agents and in combination for PanNENs.
• To assess the efficacy of this combination in various preclinical models, including cell lines, animal models, and patient-derived tumoroids.
• To explore the potential of combined PI3K and CDK4/6 inhibition as a therapeutic strategy.

Main Methods:

• Utilized well-differentiated and poorly differentiated PanNEN cell lines (INS-1E, NT-3, BON-1) in 2D and 3D spheroid cultures.
• Tested drug efficacy on primary islet microtissues from a genetic PanNET animal model (Men1-defective) and wild-type mice.
• Assessed the combination's effectiveness in patient-derived islet-like 3D tumoroids.

Main Results:

• The combination of buparlisib and ribociclib demonstrated superior anti-proliferative activity compared to individual drugs in PanNEN cell lines.
• Buparlisib induced apoptosis, while the combination effectively inhibited proliferation in preclinical models.
• The drug combination showed efficacy in a genetic PanNET animal model and in three out of four patient-derived tumoroid samples.

Conclusions:

• Combined targeting of PI3K (buparlisib) and CDK4/6 (ribociclib) is a promising therapeutic strategy for pancreatic neuroendocrine neoplasms.
• This approach shows efficacy across diverse molecular and histopathological features of PanNENs.
• Further investigation into this combination therapy is warranted for advanced or metastatic PanNENs.