Oncotarget

Research Papers:

DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance

Wolfgang Gruber, Martin Hutzinger, Dominik Patrick Elmer, Thomas Parigger, Christina Sternberg, Lukasz Cegielkowski, Mirko Zaja, Johann Leban, Susanne Michel, Svetlana Hamm, Daniel Vitt and Fritz Aberger _

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Oncotarget. 2016; 7:7134-7148. https://doi.org/10.18632/oncotarget.6910

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Abstract

Wolfgang Gruber1, Martin Hutzinger1, Dominik Patrick Elmer1, Thomas Parigger1, Christina Sternberg1, Lukasz Cegielkowski1, Mirko Zaja2, Johann Leban3, Susanne Michel2, Svetlana Hamm2, Daniel Vitt2,4 and Fritz Aberger1

1 Cancer Cluster Salzburg, Department of Molecular Biology, University of Salzburg, Salzburg, Austria

2 4SC Discovery GmbH, Planegg-Martinsried, Germany

3 Department of Pediatrics, Medical University of Vienna, Vienna, Austria

4 4SC AG, Planegg-Martinsried, Germany

Correspondence to:

Fritz Aberger, email:

Keywords: Hedgehog/GLI signaling, GLI transcription factors, DYRK1B, Smoothened drug resistance, basal cell carcinoma

Received: December 23, 2015 Accepted: January 04, 2016 Published: January 13, 2016

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.


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