title: Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma.
abstract: Purpose:Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the interleukin-1 receptor-associated kinases (IRAKs) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAKs in the pathobiology of PDAC.Experimental Design:We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small-molecule IRAK1/4 inhibitor, RNA-interference, and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-κB activity, chemoresistance, cytokine production, and growth of PDAC cellsin vitroandin vivoResults:p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. The presence of p-IRAK4 strongly correlated with phospho-NF-κB/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-κB activity, anchorage-independent growth, chemoresistance, and secretion of proinflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis.Conclusions:Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing.Clin Cancer Res; 23(7); 1748-59. ©2016 AACR.
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Daoxiang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Brett L
authors.initials: BL
authors.lastname: Knolhoff
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Lockhart
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: David G
authors.initials: DG
authors.lastname: DeNardo
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Marianna B
authors.initials: MB
authors.lastname: Ruzinova
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri. kian-huat.lim@wustl.edu.
authors.forename: Kian-Huat
authors.initials: KH
authors.lastname: Lim
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D051379:Mice; D011379:Prognosis; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D000093542:Gemcitabine