title: Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation.
abstract: Autophagy promotes tumor progression downstream of oncogenic KRAS, yet also restrains inflammation and dysplasia through mechanisms that remain incompletely characterized. Understanding the basis of this paradox has important implications for the optimal targeting of autophagy in cancer. Using a mouse model of cerulein-induced pancreatitis, we found that loss of autophagy by deletion of Atg5 enhanced activation of the IκB kinase (IKK)-related kinase TBK1 in vivo, associated with increased neutrophil and T-cell infiltration and PD-L1 upregulation. Consistent with this observation, pharmacologic or genetic inhibition of autophagy in pancreatic ductal adenocarcinoma cells, including suppression of the autophagy receptors NDP52 or p62, prolonged TBK1 activation and increased expression of CCL5, IL6, and several other T-cell and neutrophil chemotactic cytokines in vitro Defective autophagy also promoted PD-L1 upregulation, which is particularly pronounced downstream of IFNγ signaling and involves JAK pathway activation. Treatment with the TBK1/IKKε/JAK inhibitor CYT387 (also known as momelotinib) not only inhibits autophagy, but also suppresses this feedback inflammation and reduces PD-L1 expression, limiting KRAS-driven pancreatic dysplasia. These findings could contribute to the dual role of autophagy in oncogenesis and have important consequences for its therapeutic targeting. Cancer Immunol Res; 4(6); 520-30. ©2016 AACR.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Surgery and Science, Graduate of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Russell W
authors.initials: RW
authors.lastname: Jenkins
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Israel
authors.initials: I
authors.lastname: Cañadas
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kitajima
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Amir
authors.initials: A
authors.lastname: Aref
authors.affiliation: Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Cell and Developmental Biology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Arthur
authors.initials: A
authors.lastname: Brannon
authors.affiliation: Department of Surgery and Science, Graduate of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Adam
authors.initials: A
authors.lastname: Castoreno
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Tran
authors.initials: T
authors.lastname: Thai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jacob
authors.initials: J
authors.lastname: Reibel
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kwok K
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.affiliation: Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.affiliation: Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Cell and Developmental Biology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca Di Magliano
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts. dbarbie@partners.org.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
mesh_terms: D000208:Acute Disease; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001549:Benzamides / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002108:Ceruletide; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D017353:Gene Deletion; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D060890:B7-H1 Antigen; D001549:Benzamides; C503460:Ccl5 protein, mouse; C498919:Cd274 protein, mouse; D018946:Chemokine CCL5; D016207:Cytokines; D011743:Pyrimidines; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; D002108:Ceruletide; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)