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Targeting class I histone deacetylases by the novel small molecule inhibitor 4 SC ‐202 blocks oncogenic hedgehog‐ GLI signaling and overcomes smoothened inhibitor resistance
Author(s) -
Gruber Wolfgang,
Peer Elisabeth,
Elmer Dominik P.,
Sternberg Christina,
Tesanovic Suzana,
del Burgo Pedro,
Coni Sonia,
Canettieri Gianluca,
Neureiter Daniel,
Bartz René,
Kohlhof Hella,
Vitt Daniel,
Aberger Fritz
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31117
Subject(s) - smoothened , hedgehog signaling pathway , vismodegib , hedgehog , cancer research , signal transduction , effector , biology , histone deacetylase , microbiology and biotechnology , chemistry , histone , genetics , gene
Aberrant activation of Hedgehog (HH)/GLI signaling is causally involved in numerous human malignancies, including basal cell carcinoma (BCC) and medulloblastoma. HH pathway antagonists targeting smoothened (SMO), an essential effector of canonical HH/GLI signaling, show significant clinical success in BCC patients and have recently been approved for the treatment of advanced and metastatic BCC. However, rapid and frequent development of drug resistance to SMO inhibitors (SMOi) together with severe side effects caused by prolonged SMOi treatment call for alternative treatment strategies targeting HH/GLI signaling downstream of SMO. In this study, we report that 4SC‐202, a novel clinically validated inhibitor of class I histone deacetylases (HDACs), efficiently blocks HH/GLI signaling. Notably, 4SC‐202 treatment abrogates GLI activation and HH target gene expression in both SMOi‐sensitive and ‐resistant cells. Mechanistically, we propose that the inhibition of HDACs 1/2/3 is crucial for targeting oncogenic HH/GLI signaling, and that class I HDAC inhibitors either in combination with SMOi or as second‐line therapy may improve the treatment options for HH‐associated malignancies with SMOi resistance.