Abstract 181: Constitutive IRAK1/4 kinase activation contributes to NF-kB activity and chemoresistance in pancreatic cancer Free

Constitutive activation of the NF-κb transcription factor is a major molecular mechanism that contributes to the aggressive behavior and treatment resistance of pancreatic cancer. Understanding the molecular mechanisms that activate NF-κB will provide novel therapeutic opportunities to improve the dismal outcome of pancreatic cancer patients. In the present study, we showed that the Interleukin-1 Receptor-Associated Kinases 1 and 4 (IRAK1 and IRAK4) are constitutively activated in a majority of pancreatic cancer cell lines and patients samples, and are major drivers of NF-κB activity. Notably, we found that constitutive phosphorylation of IRAK4 is associated with poor patient prognosis. Suppression of IRAK1 and IRAK4 with small molecule inhibitor or RNA-interference in pancreatic cancer cells significantly reduces NF-κB activity, three-dimensional growth, invasiveness, production of inflammatory, and augment their sensitivity to chemotherapeutic agents in vitro. Notably, we showed that the NF-κB activity of pancreatic cancer cell with IRAK4 ablated using CRISPR technology can be restored with wild-type, but not kinase-dead IRAK4 mutant, supporting development of IRAK4 inhibitor as a novel therapeutic agent in pancreatic cancer. Silencing of IRAK1 or IRAK4, and more potently both, significantly abrogated the tumorigenic potential of human and murine pancreatic cancer cells as xenograft in mice. Lastly, we showed that IRAK1/4 inhibitor augments the therapeutic effect of gemcitabine in tumor-bearing mice by suppressing proliferation and increasing apoptosis of neoplastic cells, and reducing stromal fibrosis. Together, our data established IRAK4 kinase inhibitors as a promising novel class of targeted agent in pancreatic cancer.

Citation Format: Daoxiang Zhang, Lin Li, Hongmei Jiang, Jinsheng Yu, Brett Knolhoff, Richard Head, Albert C. Lockhart, David G. DeNardo, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Constitutive IRAK1/4 kinase activation contributes to NF-kB activity and chemoresistance in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 181.