Abstract
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.
Footnotes
↵9 Lead Contact: Scott A. Oakes, University of Chicago, Knapp Center for Biomedical Discovery, Rm 6124, 900 E. 57th St, Chicago, IL 60637 (Tel: 773-702-3797)
The work was supported by grants: American Cancer Society Research Scholar Award (S.A.O.); Harrington Discovery Institute Scholar-Innovator Award (S.A.O. and F.R.P.); UCSF and Onyx Oncology Innovation Alliance (S.A.O. and F.R.P.); Alfred P. Sloan Foundation (D.J.M.); Camille and Henry Dreyfus Foundation (D.J.M.); American Association of Cancer Research (S.A.O.); National Science Foundation (J.Y.Q.); NIH/NCI Brain Tumor SPORE (UCSF BTRC) the P50 CA097257 NIH/NCI Brain Tumor SPORE Grant. R01CA219815 (S.A.O.), R01EY027810 (S.A.O.; F.R.P.), U01DK108332 (S.A.O.), T32CA177555 (S.A.O.)
CONFLICT OF INTEREST D.J.M., B.J.B., F.R. P, and S.A.O. are founders, equity holders, and consultants for OptiKIRA, LLC (Cleveland, OH), a biotech company focused on treating ER-stress induced retinal degeneration.
