CDK5 Activation Drives Pancreatic Neuroendocrine Tumorigenesis and is a Therapeutic Target

Abstract

Introduction: Pancreatic neuroendocrine tumors(PNET) are frequently seen with significant morbidity/mortality. Most PNET are non-functional, yet existing animal models are functional. Therefore, they do not accurately recapitulate human disease. We hypothesize that Cdk5 activity (previously shown to be important in other neuroendocrine diseases) plays a role in PNET pathogenesis and maybe a therapeutic target. Methods: Cdk5 expression was quantified in human PNET(hPNET) tissues. hPNET cell lines were treated with Cdk5 inhibitors. Bi-transgenic mice were created with inducible Cdk5 activity under control of the tet-operon. Growing/arrested tumors were studied for phosphorylation sites that were upregulated in growing tumors. Short interfering peptides (SIPs) were generated to these targets to identify potential downstream signaling pathways. Results: All hPNET samples tested had increased Cdk5 expression(Figure A). A Cdk4/5 inhibitor(IndolamineA) affected growth of hPNET cells in a dose-dependent manner without effecting fibroblasts(Figure B). Cdk4 inhibition(IndolamineB) did not effect these cells. All transgenic mice developed PNET with most nonfunctional. Phosphoproteomic analysis identified 50 potential Cdk5 targets upregulated in growing tumors. SIPs to 15 sites inhibited growth of BON cells but not fibroblasts(Figure D, top). Six of these sites included known proteins implicated in human tumorigenesis (but unknown in hPNET). Phosphorylation of each was reduced in BON cells with Cdk5 inhibition, implicating each in PNET formation and growth. Conclusion: Aberrant Cdk5 activity is seen in all hPNET and is a potential therapeutic target. We have created the first transgenic model of PNET that behaves like human disease and have identified molecular pathways that are being activated in PNET.