HIC1-driven transcriptional dependency in GI stromal tumours

Background Kinase addiction remains a central driver even in tyrosine kinase inhibitor (TKI)-refractory GI stromal tumours (GISTs). The emergence of polyclonal secondary KIT proto-oncogene, receptor tyrosine kinase (KIT) mutations poses a major therapeutic challenge. Objective This study aimed to identify transcriptional dependencies sustaining KIT oncoprotein expression and explore their therapeutic targeting. Design We integrated genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screens and DNA methylation profiling to uncover epigenetic drivers. Multiomics analyses (chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin with sequencing, RNA-seq) and biochemical assays were employed to dissect the molecular function of the candidate transcription factor. A compound screen was conducted to identify hypermethylated in cancer 1 (HIC1)-targeting agents, and antitumour efficacy was evaluated in multiple GIST models including patient-derived xenografts (PDXs) and genetically engineered mice. Results HIC1 is identified as a critical and selective transcriptional dependency in GISTs. Paradoxically, despite its known tumour-suppressive role in other cancers, HIC1 is universally overexpressed in human GISTs due to promoter hypomethylation. Genetic overexpression of Hic1 in GIST precursor-interstitial cells of Cajal accelerates GIST growth and tumorigenesis in mice. Mechanistically, HIC1 functions as a master transcription factor that directly activates the expression of core GIST signature genes, including KIT, by binding their enhancers and promoters and recruiting RNA polymerase II. A chemical screen nominates topotecan (TPT)—an U.S. Food and Drug Administration (FDA)-approved drug—as a HIC1 suppressor. TPT directly binds ectonucleotide pyrophosphatase/phosphodiesterase 2, downregulates HIC1 and KIT, and exerts robust antitumour activity across TKI-resistant PDXs and Hic1-driven genetically engineered mice. Conclusions This comprehensive study reveals HIC1 as an oncogenic transcription factor sustaining KIT expression in GIST and uncovers a novel, clinically actionable strategy—targeting the HIC1-KIT axis with TPT—to combat TKI resistance.