EZH2 Inhibition as New Epigenetic Treatment Option for Pancreatic Neuroendocrine Neoplasms (PanNENs)

SIMPLE SUMMARY: Pancreatic neuroendocrine neoplasms (PanNENs) represent 3% of pancreatic neoplasms. Available therapies can induce stable disease only for a minority of patients. Overall survival ranges from 10 years for well-differentiated neuroendocrine tumors to as little as 10 months for more aggressive carcinomas (NECs). It has been shown that epigenetic aberrations are relevant for the development and progression of PanNENs. We found that increased expression of the methyl transferase EZH2 correlated with higher tumor grade and advanced disease status. Inhibition of EZH2 in vitro reduced cell viability and proliferation of PanNEN cell lines as well as of patient-derived islet-like tumoroids. Similarly, inhibition of EZH2 in a PanNEN transgenic mouse model reduced tumor burden. Our data indicate that EZH2 inhibition should be further investigated/considered as an epigenetic treatment for patients with high-grade PanNENs. ABSTRACT: Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN preclinical models. EZH2 expression in PanNEN patient samples (n = 172) was assessed by immunohistochemistry and correlated with clinico-pathological data. Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro. Lentiviral transduction of shRNA targeting EZH2 was performed in QGP1 cells, and cell proliferation was measured. Rip1TAG2 mice underwent GSK126 treatment for three weeks starting from week 10 of age. Primary cells isolated from PanNEN patients (n = 6) were cultivated in 3D as islet-like tumoroids and monitored for 10 consecutive days upon GSK126 treatment. Viability was measured continuously for the whole duration of the treatment. We found that high EZH2 expression correlated with higher tumor grade (p < 0.001), presence of distant metastases (p < 0.001), and shorter disease-free survival (p < 0.001) in PanNEN patients. Inhibition of EZH2 in vitro in PanNEN cell lines and in patient-derived islet-like tumoroids reduced cell viability and impaired cell proliferation, while inhibition of EZH2 in vivo in Rip1TAG2 mice reduced tumor burden. Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN.