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.

NF-κB and Pancreatic Cancer; Chapter and Verse

“…Stimulation with various agents (Figure 3), such as bacterial endotoxins or the pro-inflammatory cytokine TNF connect through their respective Toll-like receptors (TLRs) or Tumor necrosis factor receptor (TNFR) receptors on cells, including within the PDAC microenvironment with different receptorproximal signaling cascades and to the IKK complex. The role of TLRs in PDAC has recently been reviewed [76], therefore we will use TNF signaling as an example for the canonical NF-κB pathway, since TNF is also a key inflammation regulator for PDAC (reviewed [77]). TNF) to cell surface receptors (e.g., TNF-R1) trigger c-REL, NF-κB1 (p105/p50) or p65/RelA and activation of the inhibitory IKK (IκB kinase) complex.…”

“…This pathway is often dysregulated in leukemias and lymphomas resulting in elevated NF-κB activity [274,275]. Several IRAK4 inhibitors have been developed (Figure 5) and are currently being clinically evaluated for inflammatory diseases including PF-06650833, BAY-1830839 and BAY1830839, (reviewed [76,262,276]). In particular, CA-4948 a small molecule inhibitor of IRAK4 is being pursued with an ongoing phase 1/2 study for relapsed/refractory hematologic malignancies (ClinicalTrials.gov Identifier: NCT04278768) [277], although it also inhibits FLT3 [262].…”

“…For example, a mutant IκBα capable of blocking NF-κB activation in mesenchymal stromal cells in a chronic pancreatitis model showed that proliferation and apoptosis of PSCs was regulated by multiple signal transduction pathways (PPAR, MAPK, mTOR, TGF-β, NOD-like receptor, Notch, WNT, TGF-β1-SMAD-2/3, and P53) [ 132 ]. Pancreatitis is therefore likely mediated by the crosstalk of intrapancreatic protease activation and inflammation mediated by NF-κB activation within macrophages through pro-inflammatory cytokines, such as TNF (reviewed [ 76 ]). In conclusion, pancreatitis initiation, the chronic form and even PDAC development occur through a series of stages [ 102 ] and the role of NF-κB at each stage and indeed each cell type (not recapitulated by all pancreatitis models) might be disparate, a point we return to later in this review.…”

“…The detailed role of the individual NF-κB transcription factors RelA/p65, RelB, and c-Rel in PDAC development and maintenance has recently been extensively reported [ 53 ]. The role of the innate immune NF-κB pathway in relation to PDAC has also been recently extensively reviewed [ 76 ]. Therefore, we will briefly review the contribution of these NF-κB elements but focus on other developments in field relating to the transition from inflammation to PDAC.…”

“…Notably, oncogenic KRAS signaling is an important driver of NF-κB activation in PDAC [ 50 ]. An intricate crosstalk between these two pathways results in the constitutive activation of canonical NF-κB through PI3K-AKT-mTOR mediated effector phosphorylation of IKK and activation of p65/RelA (reviewed [ 76 ]). More recently, additional signaling pathways resulting in NF-κB activation have been linked to KRAS driven PDAC.…”