The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms

•Analysis of regulatory and epigenetic aberrations in the p53 network of GEP-NENs.•Focus on damage response, p53 regulation and DNA methylation for therapeutic intervention.•Discussion of current and possible treatment strategies of GEP-NENs.•Analysis of substantial problems of neuroendocrine in vitro models.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous and especially the midgut tumors currently lack effective therapy options. Actionable driver mutations as therapeutic targets are rare. Subtype specific data concerning regulatory mechanisms or epigenetic aberrations are necessary for novel clinical trials. Although the p53 protein itself is rarely mutated in GEP-NENs, epigenetic and regulatory aberrations interfere with the p53 network activity and might function as s target for novel therapeutic approaches. In this review we analyze the current knowledge about the p53 network in GEP-NENs and discuss three possible strategies that include recovering p53 function, enforcing apoptosis by genotoxic stress induction and restoring silenced gene function, based on in vitro, in vivo and clinical data.