Targeting the Unfolded Protein Response in Pancreatic Neuroendocrine Tumors

A critical regulator of the unfolded protein response (UPR), the IRE1α kinase/endoribonuclease promotes adaptation or apoptosis depending on the level of upstream endoplasmic reticulum (ER) stress. The UPR is implicated in multiple cancer types, but whether IRE1α signaling is beneficial or detrimental to tumor growth remains controversial. We hypothesized that pancreatic neuroendocrine tumors (PanNETs), which are highly secretory neoplasms prone to protein-folding stress, would be one type of cancer that would be particularly sensitive to changes in UPR signaling. We used a series of genetic and pharmacologic approaches to modulate IRE1α in xenograft and spontaneous genetic (RIP-Tag2) mouse models of PanNET. We found that IRE1α signaling is carefully titrated in PanNETs in vivo such that hyperactivating or inhibiting its enzymatic activity cripples tumor growth and survival. Importantly, we found that a monoselective IRE1α kinase inhibitor dramatically decreased tumor burden and prolonged animal survival in two preclinical PanNET models by eliminating the adaptive signals that would otherwise counteract an ER stress-induced apoptotic cascade. Here, I also present preliminary data suggesting that PanNETs may be similarly sensitive to modulation of PERK, a second regulatory arm of the UPR, as demonstrated by decreased tumor burden in response to both genetic and pharmacological inhibition of PERK. Our results provide a strong rationale for therapeutically targeting IRE1α in PanNETs and other cancers that experience high levels of ER stress, as well as further investigations of the effects of targeting PERK