Targeting class I histone deacetylases by the novel small molecule inhibitor 4SC‐202 blocks oncogenic hedgehog‐GLI signaling and overcomes smoothened inhibitor resistance. Issue 5 (6th November 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: International journal of cancer. Volume 142:Issue 5(2018)
• Page Start: 968
• Page End: 975
• Publication Date: 2017-11-06
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31117
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : 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. Abstract : What's new? Inhibition of signaling by Hedgehog polypeptide and the effector protein GLI is an effective therapeutic strategy for basal cell carcinoma and medulloblastoma. The frequent development of resistance to Hedgehog pathway inhibitors (HPI), however, calls for the identification of alternative drugs. This study identifies the class I histone deacetylase inhibitor 4SC‐202 as a novel Hedgehog/GLI antagonist. A clinically suitable small molecule, 4SC‐202, showed inhibitory efficacy, blocking GLI activation and Hedgehog target gene expression, even in cells with acquired HPI resistance. The findings suggest that 4SC‐202 could be effective against Hedgehog‐driven cancers that are refractory to standard targeted therapy.