Targeting Super-Enhancer–Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor Resistance

Author:

Sui Yi12ORCID,Wang Teng3ORCID,Mei Yanqing12ORCID,Zhu Ying12ORCID,Jiang Wenyan12ORCID,Shen Jiayi4ORCID,Yan Siyuan5ORCID,Lu Wenjie12ORCID,Zhao Kewen67ORCID,Mo Jialin12ORCID,Wang Chaochen38ORCID,Tang Yujie12ORCID

Affiliation:

1. Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 1

2. Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2

3. Centre of Biomedical Systems and Informatics, ZJU-UoE Institute, Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, China. 3

4. Shanghai Jiao Tong University, School of Life Sciences and Biotechnology, Shanghai, China. 4

5. Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. 5

6. Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 6

7. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 7

8. Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. 8

Abstract

Abstract Aberrant activation of the Hedgehog (Hh) signaling pathway plays important roles in oncogenesis and therapeutic resistance in several types of cancer. The clinical application of FDA-approved Hh-targeted smoothened inhibitors (SMOi) is hindered by the emergence of primary or acquired drug resistance. Epigenetic and transcriptional-targeted therapies represent a promising direction for developing improved anti-Hh therapies. In this study, we integrated epigenetic/transcriptional-targeted small-molecule library screening with CRISPR/Cas9 knockout library screening and identified CDK9 and CDK12, two transcription elongation regulators, as therapeutic targets for antagonizing aberrant Hh activation and overcoming SMOi resistance. Inhibition of CDK9 or CDK12 potently suppressed Hh signaling and tumor growth in various SMOi responsive or resistant Hh-driven tumor models. Systemic epigenomic profiling elucidated the Hh-driven super-enhancer (SE) landscape and identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the insulin-like growth factor (IGF) pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target in Hh-driven tumor models. Collectively, this study identifies SE-driven transcriptional dependencies that represent promising therapeutic vulnerabilities for suppressing the Hh pathway and overcoming SMOi resistance. As CDK9 and IRS inhibitors have already entered human clinical trials for cancer treatment, these findings provide comprehensive preclinical support for developing trials for Hh-driven cancers. Significance: Dissecting transcriptional dependencies driven by super-enhancers uncovers therapeutic targets in Hedgehog-driven cancers and identifies strategies for overcoming resistance to smoothened inhibitors.

Funder

National Natural Science Foundation of China

Science and Technology Commission of Shanghai Municipality

Innovative Research Team of High-Level Local University in Shanghai

China Postdoctoral Science Foundation

Shanghai Sailing Program

Shanghai Charity Foundation

Publisher

American Association for Cancer Research (AACR)

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