2. Academic Validation
  3. Inhibition of the FACT Complex Targets Aberrant Hedgehog Signaling and Overcomes Resistance to Smoothened Antagonists

Inhibition of the FACT Complex Targets Aberrant Hedgehog Signaling and Overcomes Resistance to Smoothened Antagonists

  • Cancer Res. 2021 Jun 1;81(11):3105-3120. doi: 10.1158/0008-5472.CAN-20-3186.
Jialin Mo  # 1,  Fang Liu  # 2,  Xi Sun  # 3,  Hongting Huang 4,  Kezhe Tan 1,  Xiaojing Zhao 5,  Rui Li 2,  Wenyan Jiang 2,  Yi Sui 2,  Xiaosong Chen 3,  Kunwei Shen 3,  Liye Zhang 5,  Jie Ma 6,  Kewen Zhao 7,  Yujie Tang 8
Affiliations

Affiliations

  • 1 Research Center of Translational Medicine, Shanghai Children's Hospital, State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
  • 2 Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
  • 3 Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
  • 4 Department of Hepatic Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai, P.R. China.
  • 6 Department of Pediatric Neurosurgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China. yujietang@shsmu.edu.cn zkewen@sjtu.edu.cn majie@xinhuamed.com.cn.
  • 7 Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China. yujietang@shsmu.edu.cn zkewen@sjtu.edu.cn majie@xinhuamed.com.cn.
  • 8 Research Center of Translational Medicine, Shanghai Children's Hospital, State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China. yujietang@shsmu.edu.cn zkewen@sjtu.edu.cn majie@xinhuamed.com.cn.
  • # Contributed equally.
PMID: 33853831 DOI: 10.1158/0008-5472.CAN-20-3186
Abstract

Hedgehog signaling is aberrantly activated in hematologic malignancies and solid tumors, and targeting it is a promising therapeutic strategy against these cancers. Resistance to clinically available hedgehog-targeted Smoothened inhibitor (SMOi) drugs has become a critical issue in hedgehog-driven Cancer treatment. Our previous studies identified inhibition of BET and CDK7 as two epigenetic/transcriptional-targeted therapeutic strategies for overcoming SMOi resistance, providing a promising direction for anti-hedgehog drug development. To uncover additional strategies for inhibiting aberrant Hedgehog activity, here we performed CRISPR-Cas9 screening with an single-guide RNA library targeting epigenetic and transcriptional modulators in hedgehog-driven medulloblastoma cells, combined with tumor dataset analyses. Structure specific recognition protein 1 (SSRP1), a subunit of facilitates chromatin transcription (FACT) complex, was identified as a hedgehog-induced essential oncogene and therapeutic target in hedgehog-driven Cancer. The FACT inhibitor CBL0137, which has entered clinical trials for Cancer, effectively suppressed in vitro and in vivo growth of multiple SMOi-responsive and SMOi-resistant hedgehog-driven Cancer models. Mechanistically, CBL0137 exerted anti-hedgehog activity by targeting transcription of GLI1 and GLI2, which are core transcription factors of the Hedgehog pathway. SSRP1 bound the promoter regions of GLI1 and GLI2, while CBL0137 treatment substantially disrupted these interactions. Moreover, CBL0137 synergized with BET or CDK7 inhibitors to antagonize aberrant Hedgehog pathway and growth of hedgehog-driven Cancer models. Taken together, these results identify FACT inhibition as a promising epigenetic/transcriptional-targeted therapeutic strategy for treating hedgehog-driven cancers and overcoming SMOi resistance. SIGNIFICANCE: This study identifies FACT inhibition as an anti-hedgehog therapeutic strategy for overcoming resistance to Smoothened inhibitors and provides preclinical support for initiating clinical trials of FACT-targeted drug CBL0137 against hedgehog-driven cancers.

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