Abstract 3462: Modeling drug resistance in hormone receptor positive breast cancer using patient derived organoid cultures and cancer associated fibroblasts

Abstract

Abstract Breast cancer is the most prevalent cancer among women worldwide. Estrogen receptor-positive (ER+) breast cancer constitutes roughly 70% of all breast cancers. Early-stage ER+ breast cancers usually respond well to ER-targeted therapies. However, only 20-40% of patients with advanced ER+ breast cancer respond to ER-targeted therapy. Recently, three inhibitors for the cyclin-dependent kinase 4/6 (CDK4/6) were approved as first-line and/or second-line treatment in combination with ER-targeted therapies. Unfortunately, despite initial response to the combination treatment, patients acquire resistance to both ER-targeted therapies and CDK4/6 inhibitors over time. As a result of this, the 5-year survival of women with metastatic breast cancer is 28%. A large contribution to this poor survival rate is the desmoplastic nature of the tumor microenvironment. Desmoplasia is characterized by the abnormal growth of fibroblasts and a dense extracellular matrix. The role of desmoplasia in breast cancer and its contribution to promoting a pro-tumor environment by limiting nutrients and oxygen has been extensively studied. However, the role of secreted factors such as cytokines and metabolites by cancer-associated fibroblasts (CAFs) has been poorly studied in the context of targeted drug resistance and its effects on tumor behavior. Therefore, to investigate the mechanism of stroma-mediated resistance to targeted therapies, we have propagated patient-derived organoids and CAFs from treatment-naïve and treatment-resistant ER+ breast tumors. Our data shows that conditioned media from CAFs have variable ability to drive resistance to hormone therapy and CDK4/6 inhibitors. To identify secreted factors that drive resistance, we have performed cytokine arrays and untargeted metabolomics of the CAF lines that were the strongest drivers of resistance. We have identified several cytokines, such as IL-5, IL-8 and YKL40, that were secreted by all CAF lines. Furthermore, many CAF lines secreted the TCA cycle intermediates α-ketoglutarate and succinate, which have been implicated as oncometabolites in solid tumors. Our preliminary data suggests that YKL40, and succinate induce drug resistance. Together, this suggests that these factors secreted by CAFs play a role in supporting a pro-tumor environment by promoting drug resistance. Defining this mechanism of resistance to ER-targeted therapy and CDK4/6 inhibitors will elucidate potential therapeutic targets to enhance patient response to therapy. Citation Format: JENNY HOGSTROM, Kayla Cruz, Jaymin Patel, Tejas Mehta, Angelica Warren, Taru Muranen. Modeling drug resistance in hormone receptor positive breast cancer using patient derived organoid cultures and cancer associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3462.