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Purpose: Constitutive NF-κB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required for oncogenic KRAS-induced PDAC development in mouse models. We sought to determine whether targeting IL-1α pathway would inhibit NF-κB activity and thus suppress PDAC cell growth.Experimental Design: We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-κB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell lines AsPc1, Colo357, MiaPaCa-2, and HPNE/K-rasG12V/p16sh. In vivo NF-κB activation–dependent tumorigenesis was assayed using an orthotopic nude mouse model (n = 20, 5 per group) treated with a combination of gemcitabine and rhIL-1RA.Results: rhIL-1R antagonist treatment led to a significant decrease in NF-κB activity. PDAC cells treated with rhIL-1R antagonist plus gemcitabine reduced proliferation, migration, and invasion as compared with single gemcitabine treatment. In nude mice, rhIL-1R antagonist plus gemcitabine significantly reduced the tumor burden (gemcitabine plus rhIL-1RA vs. control, P = 0.014).Conclusions: We found that anakinra, an FDA-approved drug that inhibits IL-1 receptor (IL-1R), when given with or without gemcitabine, can reduce tumor growth by inhibiting IL1α-induced NF-κB activity; this result suggests that it is a useful therapeutic approach for PDAC. Clin Cancer Res; 22(6); 1432–44. ©2015 AACR.

We found that rhIL-1RA inhibits IL-1 receptor activation and NF-κB activity. Furthermore, in PDAC cells treated with or without gemcitabine, rhIL-1RA significantly decreases proliferation, migration, invasion, and tumor burden in orthotopic nude mouse model (gemcitabine plus rhIL-1RA vs. control, P=0.014). Thus, these results suggest that IL-1RA can reduce tumor growth by inhibiting IL-1a -induced NF-kB activity; the result also suggests that IL-R is a potential surrogate therapeutic target for mutant Kras and activated NF-kB in treatment of PDAC.

Figure S5. A, Q-PCR assay of genetically engineered mice showed that the IL-1α -/- gene was knocked out.