Abstract 616: TYK2: A novel therapeutic target in triple-negative breast cancer brain metastasis

Breast cancer (BC) is one of the deadliest cancers that affect 300,000 women annually where 15-25% are Triple negative in nature and spreads quickly to the brain causing brain metastasis (TNBC-BM). Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by lack of hormone receptor expression and is known for high rates of recurrence, distant metastases, and poor clinical outcomes. The 5-year survival rate for TNBC-BM is only 9%. Current standard of care to treat TNBC-BM include whole brain radiation therapy, surgery and chemotherapy which leads to sever side effects, high level of neurotoxicity, neurological complication that leads to low survival rate and low quality of life. Because of such a low survival rate, there is an unmet clinical need to treat these patients differently to decrease neurotoxicity, and TNBC-BM cell death. In our study, we identified and characterized novel therapeutic targets and targeted pharmacologic inhibitors of natural compound origin for the treatment of TNBC-BM. Our preliminary data suggest (1) overexpression of Tyk2 ( JAK Family meber) gene in TNBC-BM compared to TNBC and TNBC lung metastasis using a PDX database. Overall Survival analysis of TNBC patients databases suggest that higher expression of Tyk2 gene and it’s downstream signaling partner gene STAT5A. Tyk2 is overexpressed in the TNBC-BM metastatic brain sample and TNBC -BM specific cell line ( BrM-831). Based on the published literature and our strong preliminary data, we hypothesize that over expression of Tyk2 promotes brain metastasis in TNBC cells through the activation of Tyk2-STA5A signaling pathway stimulating epithelial-to-mesenchymal transition, cell migration and invasion of TNBC cells, leading to tumorigenesis and metastasis in TNBC; Together, this study will demonstrate Tyk2 as a new target and Tyk2 targeted therapeutic agent will be capable of inhibiting TNBC-metastasis through blocking the activation of the Tyk2-/STAT5 molecular targets. In future, we plan to develop Tyk2 targeted drug compounds originated from natural products to treat TNBC-BM. Citation Format: Jayshree Mishra, Priyam Kumar, Narendra Kumar. TYK2: A novel therapeutic target in triple-negative breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 616.