Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of the NF-κB transcription factors is a major mechanism that drives inflammation in PDAC. While targeting this pathway is widely supported as a promising therapeutic strategy, clinical success is elusive due to a lack of safe and effective anti-NF-κB pathway therapeutics. Furthermore, the cell type-specific contribution of this pathway, specifically in neoplastic cells, stromal fibroblasts, and immune cells, has not been critically appraised. In this article, we highlighted seminal and recent literature on molecular mechanisms that drive NF-κB activity in each of these major cell types in PDAC, focusing specifically on the innate immune Toll-like/IL-1 receptor pathway. We reviewed recent evidence on the signaling interplay between the NF-κB and oncogenic KRAS signaling pathways in PDAC cells and their collective contribution to cancer inflammation. Lastly, we reviewed clinical trials on agents that target the NF-κB pathway and novel therapeutic strategies that have been proposed in preclinical studies.

Keywords: IRAK4; NF-κB; TAK1; TPL2; inflammation; pancreatic cancer.

Figure 1

Overview of receptors and signaling pathways that activate the NF-κB cascade. After recognition of their cognate ligands, IL1-R and TLR and recruit their adaptor protein, MyD88. MyD88 then associates with IRAK4 recruiting TNFR- receptor-associated factor (TRAF)6, transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1), IKK complex, and activating NF-κB, JNK and p38 MAPKs, and type-1 interferon pathways. In addition, engagement of the TNFRs recruits TNFR receptor-associated factor (TRAF)2, activating TAK1.

Figure 2

Signaling crosstalk between the KRAS and NF-κB pathways. The crosstalk of oncogenic KRAS with NF-κB pathway to promote cellular proliferation, survival, and secretion of cytokines.