Abstract C129: Fostamatinib as a STAT3 inhibitor and potential therapeutic for triple negative breast cancer and high grade serous ovarian cancer

Abstract Triple negative breast cancer (TNBC) and high grade serous ovarian cancer (HGSOC) are two highly deadly female cancers that demonstrate a strong need for new treatment strategies. TNBC and HGSOC are characterized by highly proliferative, migratory, and aggressive cancer cells that have constitutive activation of the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). In TNBC and HGSOC, STAT3 protects against apoptosis and promotes cell viability, migration, and invasion. Thus, the inhibition of STAT3 represents a promising avenue for novel TNBC and HGSOC therapeutics. Recently, the drug fostamatinib, a spleen tyrosine kinase (Syk) inhibitor, was identified as a potential STAT3 inhibitor using a virtual screen. We hypothesized that fostamatinib could be used to target STAT3 and decrease cell viability and metastasis in TNBC and HGSOC. To determine if fostamatinib inhibited STAT3 activity, western blots were performed, and we found that fostamatinib treatment strongly reduced STAT3 activation in both TNBC and HGSOC cell lines. Fostamatinib treatment also significantly reduced breast and ovarian cancer cell viability in cells grown in 2D and 3D. Since STAT3 promotes both migration and invasion, 2D migration and 3D spheroid invasion assays were performed. The 3D spheroid invasion assay measures the ability of TNBC cells to invade and move through a basement membrane extracellular matrix. The migration and invasion assays indicated that fostamatinib treatment strongly inhibits TNBC migration and invasion in both 2D and 3D models. To assess metastasis in ovarian cancer, we used a 3D mesothelial clearance assay that measures the ability of ovarian cancer spheroids to push away mesothelial cells. This process models the early steps of ovarian cancer metastasis in which ovarian cancer cells clear the mesothelial cells that line the body cavity. Data from the clearance assay indicated that ovarian cancer spheroids treated with fostamatinib significantly reduced mesothelial clearance. Currently, combination therapy with fostamatinib and cisplatin or paclitaxel is being analyzed. Our data thus far indicates that fostamatinib reduces STAT3 activation, 2D and 3D cell viability, migration and invasion in TNBC, and mesothelial clearance in HGSOC. Taken together, our data suggests that fostamatinib could be used as a new therapy to inhibit STAT3 and treat breast and ovarian cancer patients. Citation Format: Katherine E. Veronneau, Sarah R. Walker. Fostamatinib as a STAT3 inhibitor and potential therapeutic for triple negative breast cancer and high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C129.