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.
Keywords:
DYRK1B; GLI transcription factors; Hedgehog/GLI signaling; Smoothened drug resistance; basal cell carcinoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Carcinoma, Basal Cell / drug therapy
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Carcinoma, Basal Cell / genetics
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Carcinoma, Basal Cell / metabolism
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Carcinoma, Basal Cell / pathology*
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Cell Proliferation / drug effects
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Cells, Cultured
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Drug Resistance, Neoplasm*
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Dyrk Kinases
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Forkhead Transcription Factors / physiology
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Hedgehog Proteins / antagonists & inhibitors
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Humans
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Mice
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Mice, Nude
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NIH 3T3 Cells
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Skin Neoplasms / drug therapy
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Skin Neoplasms / genetics
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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Smoothened Receptor / antagonists & inhibitors
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Smoothened Receptor / genetics
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Smoothened Receptor / metabolism*
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Xenograft Model Antitumor Assays
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Zinc Finger Protein GLI1 / antagonists & inhibitors
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Zinc Finger Protein GLI1 / genetics
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Zinc Finger Protein GLI1 / metabolism*
Substances
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Antineoplastic Agents
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Forkhead Transcription Factors
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Hedgehog Proteins
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RNA, Messenger
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RNA, Small Interfering
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Smoothened Receptor
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Whn protein
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Zinc Finger Protein GLI1
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases