PT  - JOURNAL ARTICLE
AU  - Moore, Paul C.
AU  - Qi, Jenny Y.
AU  - Thamsen, Maike
AU  - Ghosh, Rajarshi
AU  - Peng, Justin
AU  - Gliedt, Micah J.
AU  - Meza-Acevedo, Rosa
AU  - Warren, Rachel E.
AU  - Hiniker, Annie
AU  - Kim, Grace E.
AU  - Maly, Dustin J.
AU  - Backes, Bradley J.
AU  - Papa, Feroz R.
AU  - Oakes, Scott A.
TI  - Parallel signaling through IRE1α and PERK regulates pancreatic neuroendocrine tumor growth and survival
AID  - 10.1101/522102
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 522102
4099  - http://biorxiv.org/content/early/2019/09/18/522102.short
4100  - http://biorxiv.org/content/early/2019/09/18/522102.full
AB  - Master 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 unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNETs) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. For the nearly 1,500 Americans diagnosed with PanNETs annually, surgery is the only potentially curative treatment; however the five-year survival is extremely low for those who develop metastatic disease. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. We then used genetic and pharmacologic approaches to modulate IRE1α and PERK in cultured cells and xenograft and spontaneous genetic (RIP-Tag2) mouse models of PanNETs. 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, thereby 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.Significance The unfolded protein response (UPR) is upregulated in human pancreatic neuroendocrine tumors and its genetic or pharmacological inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in neoplasms with elevated ER stress.