Targeting class I histone deacetylases by the novel small molecule inhibitor 4SC-202 blocks oncogenic hedgehog-GLI signaling and overcomes smoothened inhibitor resistance

Aberrant activation of Hedgehog (HH)/GLI signaling is implicated in the development of numerous human malignancies, including basal cell carcinoma (BCC) and medulloblastoma. Therapeutic strategies targeting smoothened (SMO), a key effector of canonical HH/GLI signaling, have demonstrated significant clinical efficacy in treating BCC, leading to the approval of SMO inhibitors (SMOi) for advanced and metastatic cases. However, the frequent emergence of drug resistance and the severe side effects associated with prolonged SMOi therapy highlight the need for alternative approaches targeting HH/GLI signaling downstream of SMO.

In this study, we demonstrate that 4SC-202, a novel clinically validated inhibitor of class I histone deacetylases (HDACs), effectively suppresses HH/GLI signaling. Treatment with 4SC-202 disrupts GLI activation and downregulates HH target gene expression in both SMOi-sensitive and SMOi-resistant cells. Mechanistically, we identify inhibition of HDACs 1/2/3 as critical for blocking oncogenic HH/GLI signaling. These findings suggest that class I HDAC inhibitors, either in combination with SMOi or as a second-line therapy, offer a promising strategy to enhance treatment outcomes in HH-associated malignancies with SMOi resistance.