Tyrosine kinase inhibitor (TKI) efficacy declines with successive lines of therapy, creating an urgent need for strategies that directly target KIT/platelet-derived growth factor receptor alpha (PDGFRA) dependency in GI stromal tumours (GISTs).
This study redefines HIC1 (hypermethylated in cancer 1) as an oncogenic transcription factor that is universally overexpressed in GIST and essential for sustaining KIT expression.
We demonstrate that topotecan (TPT) disrupts the HIC1-KIT axis by directly binding ectonucleotide pyrophosphatase/phosphodiesterase 2, exerting potent antitumour activity across multiple TKI-resistant models.
Our findings establish targeting transcriptional dependencies—specifically the HIC1-KIT axis—as a novel therapeutic paradigm to overcome TKI resistance.
By repurposing the FDA-approved drug TPT, this work provides a clinically actionable strategy for treating refractory GISTs.
Targeted inhibition of constitutively activated kinase oncoproteins has transformed cancer treatment.