MUC1-C DEPENDENCE FOR PROGRESSION OF PANCREATIC NEUROENDOCRINE TUMORS IDENTIFIES A DRUGGABLE TARGET FOR TREATMENT OF THIS RARE CANCER

Patients with rare pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression associates with (i) advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development. RNA Seq in pNET Cell line with MUC1-C shRNA silencing. We conpared DMSO and DOX treatment cells for differential gene expression analysis. MUC1shRNA (MISSION shRNA TRCN0000122938; Sigma, St. Louis, MO, USA) was inserted into the pLKO-tet-puro vector (Plasmid #21915; Addgene, Cambridge, MA, USA) . Vector-transduced cells were selected for growth in 1–2 μg/ml puromycin. Cells were treated with 0.1% DMSO as the vehicle control or 500 ng/ml doxycycline (DOX; Millipore Sigma).