title: DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance.
abstract: A wide range of human malignancies displays aberrant activation of Hedgehog (HH)/GLI signaling, including cancers of the skin, brain, gastrointestinal tract and hematopoietic system. Targeting oncogenic HH/GLI signaling with small molecule inhibitors of the essential pathway effector Smoothened (SMO) has shown remarkable therapeutic effects in patients with advanced and metastatic basal cell carcinoma. However, acquired and de novo resistance to SMO inhibitors poses severe limitations to the use of SMO antagonists and urgently calls for the identification of novel targets and compounds.Here we report on the identification of the Dual-Specificity-Tyrosine-Phosphorylation-Regulated Kinase 1B (DYRK1B) as critical positive regulator of HH/GLI signaling downstream of SMO. Genetic and chemical inhibition of DYRK1B in human and mouse cancer cells resulted in marked repression of HH signaling and GLI1 expression, respectively. Importantly, DYRK1B inhibition profoundly impaired GLI1 expression in both SMO-inhibitor sensitive and resistant settings. We further introduce a novel small molecule DYRK1B inhibitor, DYRKi, with suitable pharmacologic properties to impair SMO-dependent and SMO-independent oncogenic GLI activity. The results support the use of DYRK1B antagonists for the treatment of HH/GLI-associated cancers where SMO inhibitors fail to demonstrate therapeutic efficacy.
authors.affiliation: Cancer Cluster Salzburg, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gruber
authors.affiliation: Cancer Cluster Salzburg, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Hutzinger
authors.affiliation: Cancer Cluster Salzburg, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Dominik Patrick
authors.initials: DP
authors.lastname: Elmer
authors.affiliation: Cancer Cluster Salzburg, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Parigger
authors.affiliation: Cancer Cluster Salzburg, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Sternberg
authors.affiliation: Cancer Cluster Salzburg, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Cegielkowski
authors.affiliation: 4SC Discovery GmbH, Planegg-Martinsried, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Zaja
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Leban
authors.affiliation: 4SC Discovery GmbH, Planegg-Martinsried, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Michel
authors.affiliation: 4SC Discovery GmbH, Planegg-Martinsried, Germany.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Hamm
authors.affiliation: 4SC Discovery GmbH, Planegg-Martinsried, Germany.|4SC AG, Planegg-Martinsried, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vitt
authors.affiliation: Cancer Cluster Salzburg, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Aberger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D051858:Forkhead Transcription Factors / Q000502:physiology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D000970:Antineoplastic Agents; D051858:Forkhead Transcription Factors; D053823:Hedgehog Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1; D000097603:Dyrk Kinases; C090140:Whn protein
keywords: DYRK1B; GLI transcription factors; Hedgehog/GLI signaling; Smoothened drug resistance; basal cell carcinoma