Landscape of gene fusions in hormone receptor-positive breast cancer reveals ADK fusions as drivers of progression and potential therapeutic targets.

Gene fusions are becoming critical oncogenic drivers with potential therapeutic relevance across various cancers. However, their roles and clinical implications in breast cancer remain largely unexplored. In this study, we leveraged a large-scale multiomics cohort and a drug screening platform for breast cancer to systematically profile gene fusions. We identified ADK fusion genes as novel and recurrent drivers in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2‒) breast cancer. Functionally, the most commonly occurring ADK fusion gene, KAT6B::ADK, enhances metastatic potential and confers tamoxifen resistance. Mechanistically, KAT6B::ADK activates ADK kinase activity through liquid‒liquid phase separation, triggering the activation of an integrated stress response signaling pathway. Notably, patient-derived organoids harboring KAT6B::ADK from HR+/HER2‒ breast cancer demonstrate increased sensitivity to ADK inhibitors, underscoring the therapeutic potential of this fusion gene. Our findings establish ADK fusions as therapeutic targets in HR+/HER2‒ breast cancer, offering new avenues for innovative precision treatment strategies in this patient population.