CAF-secreted succinate drives resistance to CDk4/6 inhibitors in luminal breast cancer
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Abstract
Breast cancer is the leading cause of cancer-related death in women globally. It is a complex disease with several subtypes, and the treatment approach depends on the subtype. Approximately 80% of newly diagnosed cases will be hormone receptor-positive (HR+) and many of these patients will have recurrent, metastatic disease within 20 years of diagnosis. CDK4/6 inhibitors are a frontline therapy for HR+ breast cancer that has spread beyond the primary site. However, drug resistance often develops and there are limited second-line therapies. Research into the mechanisms driving CDK4/6 inhibitor resistance is ongoing, but the tumor microenvironment is known to play a critical role in breast cancer progression and drug resistance. In this study, we use a primary matched cancer-associated fibroblast and patient-derived organoid model to show that CDK4/6 inhibitor resistance is driven by CAF-secreted succinate. We further establish the expression and localization of a receptor, SUCNR1, and SLC13 co-transporters that are known to interact with succinate in HR+ breast cancer cells and PDOs. Succinate has recently been characterized as an oncometabolite and its accumulation can affect the epigenetic and transcriptional landscape of the cell, leading to alterations in cell signaling, metabolism, and overall survival. Here we show that succinate may have a novel mechanism of influencing the cell as succinate was not uptaken and SUCNR1 expression was localized to the cytosol.