Targeting resistance to Smoothened antagonists by FACT inhibition

ABSTRACT: Resistance to clinically available targeted drugs has become a critical issue in hedgehog-driven cancer treatment. Our previous studies have demonstrated two epigenetic/transcriptional targeted therapeutic strategies, BET inhibition and CDK7 inhibition, could overcome both primary and acquired resistance to Smoothened inhibitor (SMOi) drugs, providing a promising direction for novel anti-hedgehog drug development. In this study, we performed CRISPR-Cas9 screening of epigenetic/transcriptional targeted sgRNA library in hedgehog-driven medulloblastoma (SHH-MB) cells and combined with tumor dataset analyses to identify other potential epigenetic/transcriptional targeted strategies for treating aberrant hedgehog pathway and overcoming SMOi-resistance. Our results demonstrated structure specific recognition protein 1 (SSRP1), a subunit of Facilitates Chromatin Transcription (FACT) complex, was a hedgehog-induced essential oncogene and therapeutic target of hedgehog-driven cancer. FACT inhibitor CBL0137, which has entered human clinical trials against cancer, could effectively suppress multiple mouse and human hedgehog-driven cancer models that are either SMOi-responsive or -resistant both in vitro and in vivo. Mechanistically, CBL0137 exerted its anti-hedgehog activity mainly through targeting the transcription of GLI1/2, which are core transcription factors of hedgehog pathway. ChIP-qPCR analyses further revealed SSRP1 could bind to the promoter regions of GLI1/2, while CBL0137 treatment substantially disrupted these interactions. Moreover, CBL0137 could work synergistically with BET inhibitor or CDK7 inhibitor on antagonizing aberrant hedgehog pathway and growth of either SMOi-responsive or -resistant hedgehog-driven cancer models. Taken together, our study identified FACT inhibition as another promising epigenetic/transcriptional targeted therapeutic strategy for treating hedgehog-driven cancer and overcoming SMOi-resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE171685 | GEO | 2021/07/08

REPOSITORIES: GEO