dataset
posted on 2024-08-15, 07:28 authored by Yi Sui, Teng Wang, Yanqing Mei, Ying Zhu, Wenyan Jiang, Jiayi Shen, Siyuan Yan, Wenjie Lu, Kewen Zhao, Jialin Mo, Chaochen Wang, Yujie Tang Supplementary Table S1. PCR primers for NGS. The primer sequences for amplifying sgRNA sequences from genome DNA for NGS assays.
Funding
National Natural Science Foundation of China (NSFC)
Science and Technology Commission of Shanghai Municipality (STCSM)
Innovative Research Team of High-Level Local University in Shanghai (Innovative Research Team of High-Level Local Universities in Shanghai)
China Postdoctoral Science Foundation (China Postdoctoral Foundation Project)
Shanghai Sailing Program
Shanghai Charity Foundation
History
ARTICLE 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.
