Journal
ONCOTARGET
Volume 7, Issue 6, Pages 7134-7148Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6910
Keywords
Hedgehog/GLI signaling; GLI transcription factors; DYRK1B; Smoothened drug resistance; basal cell carcinoma
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Funding
- priority program Biosciences and Health of the Paris-Lodron University of Salzburg
- Austrian Science Fund [P20652, P25629]
- Marie Curie Initial Training Network HEALING
- Austrian Science Fund (FWF) [P20652, W1213, P25629] Funding Source: Austrian Science Fund (FWF)
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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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