Parallel signaling through IRE1α and PERK regulates pancreatic neuroendocrine tumor growth and survival

Critical regulators of the unfolded protein response (UPR), IRE1α and PERK promote adaptation or apoptosis depending on levels of endoplasmic reticulum (ER) stress. While the UPR is activated in many cancers, its effects on tumor growth remain controversial. We used genetic and pharmacologic approaches to modulate IRE1α and PERK in cultured cells and xenograft and spontaneous genetic (RIP-Tag2) mouse models of pancreatic neuroendocrine tumors (PanNETs), highly secretory neoplasms prone to ER stress. We found that UPR signaling is optimized for adaptation and that inhibiting either IRE1α or PERK leads to hyperactivation and apoptotic signaling through the reciprocal arm, halting tumor growth and survival. Our results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers experiencing elevated ER stress.