Abstract 600: Targeting STAT pathways with oridonin derivatives to suppress triple negative breast cancer

Abstract Breast cancer remains the most common cancer type and second leading cause of cancer related deaths among women in the U.S. Despite progress in detection, surveillance, and targeted therapies, aggressive subtypes like triple-negative breast cancer (TNBC), along with challenges such as drug resistance and disease recurrence, remain significant clinical hurdles. To address these unmet needs in TNBC treatment, our group has developed a series of oridonin-derived analogs (oridonalogs), including CYD0618. These analogs exhibit enhanced drug-like properties and significantly improved potency against various cancers in both in vitro and in vivo models. This study aims to characterize the mechanism of action of CYD0618 against TNBC cells. Our findings demonstrate that CYD0618 effectively reduces the proliferation of TNBC cells in vitro with IC50s at the nanomolar level. Additionally, CYD0618 exhibits high potency against TNBC in vivo, significantly suppressing tumor growth and prolonging survival in a xenograft mouse model. Preliminary results reveal that CYD0618 inhibits activation of STAT3, a key transcription factor involved in proliferation, survival, and transformation of epithelial cells. Given that STAT3 is constitutively active in ∼70% of human cancers, there has been a tremendous effort to develop STAT3 targeting therapies; however, none have achieved FDA approval. In addition to STAT3, our study shows that CYD0618 also suppresses other STAT family transcription factors. Compared to selective STAT3 degradation by PROTAC treatment, poly-STAT targeting by CYD0618 exhibits superior activity against TNBC cells. These findings identify CYD0618 as a novel poly-STAT inhibitor with promising activity against TNBC. Citation Format: Gabrielle Vontz,Jun Li,Zhipin Liang,Jia Zhou,Qiang Shen. Targeting STAT pathways with oridonin derivatives to suppress triple negative breast cancer [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 600.