ADK Fusions Emerge as Key Drivers and Therapeutic Targets in HR+/HER2- Breast Cancer
Source PublicationCell Discovery
Primary AuthorsOu-Yang, Ma, Lin et al.
Gene fusions, molecular aberrations that often drive tumor growth and progression, have emerged as crucial targets for cancer therapies in various cancer types. However, their specific roles and clinical significance in breast cancer, especially in identifying therapeutically actionable fusions, have remained largely unexplored. Addressing this gap, a recent study leveraged a comprehensive multiomics cohort and a drug screening platform to systematically profile gene fusions in breast cancer, aiming to uncover novel drivers and potential therapeutic vulnerabilities.
The research successfully identified ADK fusion genes as novel and recurrent drivers within hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer. A key discovery was the most commonly occurring ADK fusion, KAT6B::ADK, which was found to enhance metastatic potential and confer tamoxifen resistance. Mechanistically, KAT6B::ADK activates ADK kinase activity through liquid-liquid phase separation, triggering the activation of an integrated stress response signaling pathway.
Crucially, the study highlighted the therapeutic potential of these findings. Patient-derived organoids harboring the KAT6B::ADK fusion from HR+/HER2− breast cancer exhibited increased sensitivity to ADK inhibitors. This compelling evidence underscores that ADK fusions are not just oncogenic drivers but also viable therapeutic targets. The findings establish new avenues for innovative precision treatment strategies specifically for this patient population.
As lead author Ou-Yang notes in the paper, "Therefore, gene fusion identification is valuable not only for understanding the biological mechanisms of tumorigenesis but also for providing significant clinical opportunities to treat cancers." By uncovering these previously rare-to-identify pathological implications of gene fusions, this study highlights their potential as predictive biomarkers and therapeutic targets, paving the way for targeted therapies tailored to the genetic landscape of breast cancer.