MEN1 Deficiency‐Driven Activation of the β‐Catenin‐MGMT Axis Promotes Pancreatic Neuroendocrine Tumor Growth and Confers Temozolomide Resistance

Abstract O6‐methylguanine DNA methyltransferase (MGMT) removes alkyl adducts from the guanine O6 position (O 6 ‐MG) and repairs DNA damage. High MGMT expression results in poor response to temozolomide (TMZ). However, the biological importance of MGMT and the mechanism underlying its high expression in pancreatic neuroendocrine tumors (PanNETs) remain elusive. Here, it is found that MGMT expression is highly elevated in PanNET tissues compared with paired normal tissues and negatively associated with progression‐free survival (PFS) time in patients with PanNETs. Knocking out MGMT inhibits cancer cell growth in vitro and in vivo. Ectopic MEN1 expression suppresses MGMT transcription in a manner that depends on β‐Catenin nuclear export and degradation. The Leucine 267 residue of MEN1 is crucial for regulating β‐Catenin‐MGMT axis activation and chemosensitivity to TMZ. Interference with β‐Catenin re‐sensitizes tumor cells to TMZ and significantly reduces the cytotoxic effects of high‐dose TMZ treatment, and MGMT overexpression counteracts the effects of β‐Catenin deficiency. This study reveals the biological importance of MGMT and a new mechanism by which MEN1 deficiency regulates its expression, thus providing a potential combinational strategy for treating patients with TMZ‐resistant PanNETs.