American Association for Cancer Research
00085472can191116-sup-220286_2_supp_5824257_pz2tvt.pdf (949.68 kB)

Figure S5 from Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival

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journal contribution
posted on 2023-03-31, 02:43 authored by Paul C. Moore, Jenny Y. Qi, Maike Thamsen, Rajarshi Ghosh, Justin Peng, Micah J. Gliedt, Rosa Meza-Acevedo, Rachel E. Warren, Annie Hiniker, Grace E. Kim, Dustin J. Maly, Bradley J. Backes, Feroz R. Papa, Scott A. Oakes

KIRA8 and GSK-PKI induce distinct apoptotic markers in INS1 tumors


American Cancer Society Research Scholar Award

Carcinoid Tumor and Pancreatic Neuroendocrine Tumor Research

Neuroendocrine Tumor Research Foundation

Harrington Discovery Institute Scholar-Innovator





Master regulators of the unfolded protein response (UPR), IRE1α and PERK, promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. Although the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNET) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. 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. Genetic and pharmacologic modulation of IRE1α and PERK in cultured cells, xenograft, and spontaneous genetic (RIP-Tag2) mouse models of PanNETs revealed that UPR signaling was optimized for adaptation and that inhibiting either IRE1α or PERK led to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. These results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers with elevated ER stress. The UPR is upregulated in pancreatic neuroendocrine tumors and its inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in these cancers.