DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance
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...
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| Veröffentlicht in: | Oncotarget 2016-02, Vol.7 (6), p.7134-7148 |
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| creator | Gruber, Wolfgang Hutzinger, Martin Elmer, Dominik Patrick Parigger, Thomas Sternberg, Christina Cegielkowski, Lukasz Zaja, Mirko Leban, Johann Michel, Susanne Hamm, Svetlana Vitt, Daniel Aberger, Fritz |
| description | 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. |
| doi_str_mv | 10.18632/oncotarget.6910 |
| format | Article |
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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.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.6910</identifier><identifier>PMID: 26784250</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Blotting, Western ; Carcinoma, Basal Cell - drug therapy ; Carcinoma, Basal Cell - genetics ; Carcinoma, Basal Cell - metabolism ; Carcinoma, Basal Cell - pathology ; Cell Proliferation - drug effects ; Cells, Cultured ; Drug Resistance, Neoplasm ; Dyrk Kinases ; Forkhead Transcription Factors - physiology ; Hedgehog Proteins - antagonists & inhibitors ; Hedgehog Proteins - genetics ; Hedgehog Proteins - metabolism ; Humans ; Mice ; Mice, Nude ; NIH 3T3 Cells ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Protein Serine-Threonine Kinases - antagonists & inhibitors ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Protein-Tyrosine Kinases - genetics ; Protein-Tyrosine Kinases - metabolism ; Real-Time Polymerase Chain Reaction ; Research Paper ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; RNA, Small Interfering - genetics ; Skin Neoplasms - drug therapy ; Skin Neoplasms - genetics ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology ; Smoothened Receptor - antagonists & inhibitors ; Smoothened Receptor - genetics ; Smoothened Receptor - metabolism ; Xenograft Model Antitumor Assays ; Zinc Finger Protein GLI1 - antagonists & inhibitors ; Zinc Finger Protein GLI1 - genetics ; Zinc Finger Protein GLI1 - metabolism</subject><ispartof>Oncotarget, 2016-02, Vol.7 (6), p.7134-7148</ispartof><rights>Copyright: © 2016 Gruber et al. 2016</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-cbf910e98f30068e46d65e448377563546f97a3c57d283a797cd56d3c233af413</citedby><cites>FETCH-LOGICAL-c424t-cbf910e98f30068e46d65e448377563546f97a3c57d283a797cd56d3c233af413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872774/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872774/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26784250$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gruber, Wolfgang</creatorcontrib><creatorcontrib>Hutzinger, Martin</creatorcontrib><creatorcontrib>Elmer, Dominik Patrick</creatorcontrib><creatorcontrib>Parigger, Thomas</creatorcontrib><creatorcontrib>Sternberg, Christina</creatorcontrib><creatorcontrib>Cegielkowski, Lukasz</creatorcontrib><creatorcontrib>Zaja, Mirko</creatorcontrib><creatorcontrib>Leban, Johann</creatorcontrib><creatorcontrib>Michel, Susanne</creatorcontrib><creatorcontrib>Hamm, Svetlana</creatorcontrib><creatorcontrib>Vitt, Daniel</creatorcontrib><creatorcontrib>Aberger, Fritz</creatorcontrib><title>DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>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.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Blotting, Western</subject><subject>Carcinoma, Basal Cell - drug therapy</subject><subject>Carcinoma, Basal Cell - genetics</subject><subject>Carcinoma, Basal Cell - metabolism</subject><subject>Carcinoma, Basal Cell - pathology</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Drug Resistance, Neoplasm</subject><subject>Dyrk Kinases</subject><subject>Forkhead Transcription Factors - physiology</subject><subject>Hedgehog Proteins - antagonists & inhibitors</subject><subject>Hedgehog Proteins - genetics</subject><subject>Hedgehog Proteins - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>NIH 3T3 Cells</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein Serine-Threonine Kinases - genetics</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Protein-Tyrosine Kinases - genetics</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Research Paper</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Small Interfering - genetics</subject><subject>Skin Neoplasms - drug therapy</subject><subject>Skin Neoplasms - genetics</subject><subject>Skin Neoplasms - metabolism</subject><subject>Skin Neoplasms - pathology</subject><subject>Smoothened Receptor - antagonists & inhibitors</subject><subject>Smoothened Receptor - genetics</subject><subject>Smoothened Receptor - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Zinc Finger Protein GLI1 - antagonists & inhibitors</subject><subject>Zinc Finger Protein GLI1 - genetics</subject><subject>Zinc Finger Protein GLI1 - metabolism</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkctLAzEQxoMoWrR3T5Kjl9XdPHcvgs9aLAg-Dp5Cmsx2I-2mJqnif-_Waq1zyUC-7zczfAgdFvlJUQpKTn1rfNJhAulEVEW-hXpFxaqMcE63N_o91I_xNe-KM1mSahftESFLRnjeQ83Vy8NdcYF1xKmBoOewSM7gFRa7Ft-CnUDjJ6eD0TCzMIfWQpuw0a2BgA1MpxF_uNTgx5n3HaIF29kaN3bJBxwgupiW2gO0U-tphP7Pu4-eb66fLm-z0f1geHk-ygwjLGVmXHenQFXWNM9FCUxYwYGxkkrJBeVM1JXU1HBpSUm1rKSxXFhqCKW6ZgXdR2cr7nwxnoE13bJBT9U8uJkOn8prp_7_tK5RE_-uWCmJlKwDHP8Agn9bQExq5uLyTt2CX0RVSCmoFITTTpqvpCb4GAPU6zFFrr4zUn8ZqWVGneVoc7214TcR-gVujJEJ</recordid><startdate>20160209</startdate><enddate>20160209</enddate><creator>Gruber, Wolfgang</creator><creator>Hutzinger, Martin</creator><creator>Elmer, Dominik Patrick</creator><creator>Parigger, Thomas</creator><creator>Sternberg, Christina</creator><creator>Cegielkowski, Lukasz</creator><creator>Zaja, Mirko</creator><creator>Leban, Johann</creator><creator>Michel, Susanne</creator><creator>Hamm, Svetlana</creator><creator>Vitt, Daniel</creator><creator>Aberger, Fritz</creator><general>Impact Journals LLC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160209</creationdate><title>DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance</title><author>Gruber, Wolfgang ; Hutzinger, Martin ; Elmer, Dominik Patrick ; Parigger, Thomas ; Sternberg, Christina ; Cegielkowski, Lukasz ; Zaja, Mirko ; Leban, Johann ; Michel, Susanne ; Hamm, Svetlana ; Vitt, Daniel ; Aberger, Fritz</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-cbf910e98f30068e46d65e448377563546f97a3c57d283a797cd56d3c233af413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Blotting, Western</topic><topic>Carcinoma, Basal Cell - drug therapy</topic><topic>Carcinoma, Basal Cell - genetics</topic><topic>Carcinoma, Basal Cell - metabolism</topic><topic>Carcinoma, Basal Cell - pathology</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>Drug Resistance, Neoplasm</topic><topic>Dyrk Kinases</topic><topic>Forkhead Transcription Factors - physiology</topic><topic>Hedgehog Proteins - antagonists & inhibitors</topic><topic>Hedgehog Proteins - genetics</topic><topic>Hedgehog Proteins - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>NIH 3T3 Cells</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein Serine-Threonine Kinases - genetics</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Protein-Tyrosine Kinases - genetics</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Research Paper</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Small Interfering - genetics</topic><topic>Skin Neoplasms - drug therapy</topic><topic>Skin Neoplasms - genetics</topic><topic>Skin Neoplasms - metabolism</topic><topic>Skin Neoplasms - pathology</topic><topic>Smoothened Receptor - antagonists & inhibitors</topic><topic>Smoothened Receptor - genetics</topic><topic>Smoothened Receptor - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Zinc Finger Protein GLI1 - antagonists & inhibitors</topic><topic>Zinc Finger Protein GLI1 - genetics</topic><topic>Zinc Finger Protein GLI1 - metabolism</topic><toplevel>online_resources</toplevel><creatorcontrib>Gruber, Wolfgang</creatorcontrib><creatorcontrib>Hutzinger, Martin</creatorcontrib><creatorcontrib>Elmer, Dominik Patrick</creatorcontrib><creatorcontrib>Parigger, Thomas</creatorcontrib><creatorcontrib>Sternberg, Christina</creatorcontrib><creatorcontrib>Cegielkowski, Lukasz</creatorcontrib><creatorcontrib>Zaja, Mirko</creatorcontrib><creatorcontrib>Leban, Johann</creatorcontrib><creatorcontrib>Michel, Susanne</creatorcontrib><creatorcontrib>Hamm, Svetlana</creatorcontrib><creatorcontrib>Vitt, Daniel</creatorcontrib><creatorcontrib>Aberger, Fritz</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gruber, Wolfgang</au><au>Hutzinger, Martin</au><au>Elmer, Dominik Patrick</au><au>Parigger, Thomas</au><au>Sternberg, Christina</au><au>Cegielkowski, Lukasz</au><au>Zaja, Mirko</au><au>Leban, Johann</au><au>Michel, Susanne</au><au>Hamm, Svetlana</au><au>Vitt, Daniel</au><au>Aberger, Fritz</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2016-02-09</date><risdate>2016</risdate><volume>7</volume><issue>6</issue><spage>7134</spage><epage>7148</epage><pages>7134-7148</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><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.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>26784250</pmid><doi>10.18632/oncotarget.6910</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Agents - pharmacology Apoptosis - drug effects Blotting, Western Carcinoma, Basal Cell - drug therapy Carcinoma, Basal Cell - genetics Carcinoma, Basal Cell - metabolism Carcinoma, Basal Cell - pathology Cell Proliferation - drug effects Cells, Cultured Drug Resistance, Neoplasm Dyrk Kinases Forkhead Transcription Factors - physiology Hedgehog Proteins - antagonists & inhibitors Hedgehog Proteins - genetics Hedgehog Proteins - metabolism Humans Mice Mice, Nude NIH 3T3 Cells Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism Real-Time Polymerase Chain Reaction Research Paper Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics RNA, Small Interfering - genetics Skin Neoplasms - drug therapy Skin Neoplasms - genetics Skin Neoplasms - metabolism Skin Neoplasms - pathology Smoothened Receptor - antagonists & inhibitors Smoothened Receptor - genetics Smoothened Receptor - metabolism Xenograft Model Antitumor Assays Zinc Finger Protein GLI1 - antagonists & inhibitors Zinc Finger Protein GLI1 - genetics Zinc Finger Protein GLI1 - metabolism |
| title | DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance |
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