Constitutive IRAK4 Activation Underlies Poor Prognosis And Chemoresistance In Pancreatic Ductal Adenocarcinoma: Beyond the Abstract

To date, the prognosis for pancreatic ductal adenocarcinoma (PDAC) remains dismal with a 5-year survival rate of PDAC is 8%, which is the lowest among all cancer types. Current standard-of-care treatments consist of strong combinatorial chemotherapy regimens including FOLFIRINOX and Gemcitabine/Nab-paclitaxel, provides short-lived benefit to only a subset of patients(1). An important molecular mechanism that contributes to the refractory nature of PDAC is constitutive activation the NF-B transcription factors. However, therapeutic targeting of key components of the NF-B pathway with IKKor NF-B inhibitors is hampered by significant clinical toxicities due to the universal role of these proteins in normal cellular function, underscoring an urgent need for novel strategies to inhibit this pathway.

In this study(2), we found that PDAC cells frequently upregulate the NF-B activity by summoning the innate immune pathway through activation of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4). Notably, activation of IRAK4 strongly portends high post-surgical relapse and poor prognosis in PDAC patients who have undergone surgical resection. We showed that inhibiting IRAK4 significantly lowers the NF-B activity in PDAC cells and augments the killing effect of chemotherapy in vivo and in vitro, and established IRAK4 as a novel therapeutic target. 

Our studies raise two novel research directions that need to be pursued. First, mechanisms that activate IRAK4 remain elusive. Studies from other groups showed that engagement of the Toll-like receptor (TLR) and Interleukin-1-Receptor family members, key receptors that activate IRAK4, may induce an inflammatory response through NF-B in pancreatic cancer mouse models(3, 4). Our results further validate these findings and strengthen the suspicion that damage- or pathogen-associated molecular patterns released by dead cells or microbes within the tumor microenvironment may be a major culprit that contribute to the aggressive nature of PDAC. Second, our studies suggest that constitutive activation of IRAK4 is probably a major mechanism that fosters the intensely fibrotic (or desmoplastic) stroma that renders chemotherapy and immunotherapy ineffective. From the translational standpoint, vigorous testing of IRAK4 inhibitors with clinical potential should be immediately performed in combination with chemotherapy or immunotherapy in preclinical mouse models.

Written by: Hongmei Jiang PhD and Kian-Huat Lim, MD, PhD

References:
1. Teague A, Lim KH, Wang-Gillam A. Advanced pancreatic adenocarcinoma: a review of current treatment strategies and developing therapies. Ther Adv Med Oncol. 2015;7(2):68-84.

2. Zhang D, Li L, Jiang H, Knolhoff B, Lockhart AC, Wang-Gillam A, et al. Constitutive IRAK4 Activation Underlies Poor Prognosis And Chemoresistance In Pancreatic Ductal Adenocarcinoma. Clin Cancer Res. 2016.

3. Zambirinis CP, Levie E, Nguy S, Avanzi A, Barilla R, Xu Y, et al. TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. J Exp Med. 2015;212(12):2077-94.

4. Ochi A, Graffeo CS, Zambirinis CP, Rehman A, Hackman M, Fallon N, et al. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J Clin Invest. 2012;122(11):4118-29.