Introduction: Pancreatic cancer is the fourth leading cause of adult cancer mortality in the USA. It represents one of the greatest challenges in cancer treatment. The NF-κB transcriptional factors are constitutively activated in the majority of pancreatic cancers and are involved in the regulation of numerous aspects of tumor development and progression. NF-κB and the signaling cascades that regulate its activity have thus become attractive targets for novel therapeutic approaches for pancreatic cancer.

Areas covered: This review describes and discusses the most important advances in the comprehension of the complex molecular biology of NF-κB, as well as the development of novel NF-κB-targeting strategies for the treatment of pancreatic cancer.

Expert opinion: Although the inhibition of NF-κB, especially when combined with more classic chemotherapeutic drugs, could be a promising therapeutic strategy, direct targeting NF-κB still faces important challenges. In the future, targeting nonredundant cytosolic mediators of the activation of NF-κB – such as TNF receptor associated factor family member-associated NF-κB activator -binding kinase 1 (TBK1) and TGF-beta activated kinase 1 (TAK1) – could represent a better approach to inhibit key processes in pancreatic tumor cells and make a difference for this devastating disease.