Lansoprazole Enhances Everolimus Efficacy Through <scp>DDIT3</scp> ‐Mediated <scp>PI3K</scp> / <scp>AKT</scp> /mTOR Pathway Inhibition in Pancreatic Neuroendocrine Neoplasms Proliferation

Pancreatic neuroendocrine neoplasms (PanNENs) represent a rare and heterogeneous group of tumors with diverse biological behaviors and clinical outcomes, posing significant therapeutic challenges. Recent studies have suggested that certain proton pump inhibitors, including Lansoprazole, may possess direct anti-tumor properties beyond their classical role in acid suppression; however, their specific effects and molecular mechanisms in PanNENs remain largely unexplored. This study aims to investigate the anti-proliferative effects and elucidate the underlying molecular mechanisms of Lansoprazole in PanNEN models. Our findings demonstrate that Lansoprazole significantly upregulates the expression of DNA Damage Inducible Transcript 3 (DDIT3), a key stress-induced transcription factor. This upregulation leads to the subsequent inhibition of the oncogenic PI3K/AKT/mTOR signaling pathway, a central driver of cell growth and proliferation, resulting in marked suppression of PanNEN cell proliferation in vitro. Furthermore, we explored combination therapy strategies and found that Lansoprazole synergizes with everolimus, an established mTOR inhibitor used in PanNEN treatment. This combination enhances overall anti-tumor efficacy, suggesting a promising synergistic therapeutic strategy for PanNENs. These results not only reveal a novel, drug-repurposing approach for targeting PanNENs but also provide a mechanistic rationale for combining Lansoprazole with standard targeted therapies to improve patient outcomes.