Abstract 3328: Oridonin derivative compounds target STATs to inhibit triple-negative breast cancer

Abstract Breast cancer remains the second leading cause of cancer related deaths in women. Despite the development of targeted treatments and immunotherapies, triple-negative breast cancer (TNBC) continues to evade effective treatment. TNBC lacks sufficient expression of druggable markers, ER, PR, and Her2, and exhibits especially aggressive characteristics including later diagnosis, lower survival rate, and higher rates of metastasis and reoccurrence. Currently, cytotoxic chemotherapy and radiation remain the standard of care for TNBC. Our work utilizes compounds from nature to develop therapies for TNBC with improved efficacy and safety. Oridonin, a natural kaurene-type diterpenoid enriched in the medicinal herb Rabdosia rubescens, is a promising anticancer agent, but exhibits limited bioavailability and potency. Our team successfully developed oridonin derivative CYD0618 compound that exhibits significantly improved solubility and anticancer activity. This study aims to characterize the mechanism of action of CYD0618 on TNBC cells. We found that CYD0618 reduces the proliferation of TNBC cells in vitro with IC50s at the nanomolar level. We also found CYD0618 has high potency against TNBC in vivo. Within a xenograft mouse model, CYD0618 suppresses the growth of TNBC tumors and extends animal survival. Using Western blot to probe for putative targets, we found CYD0618 reduces activation of STAT3, a transcription factor critically involved in proliferation, survival, and transformation of epithelial cells. Because STAT3 is constitutively active in ~70% of human cancers, there has been a tremendous effort to develop STAT3 targeting therapies; however, none has achieved FDA approval. In addition to STAT3, we show CYD0618 also suppresses other STAT transcription factors. Compared to selective STAT3 degradation by PROTAC treatment, poly-STAT targeting by CYD0618 exhibits superior activity against TNBC cells. Our study identifies CYD0618 as a novel poly-STAT inhibitor with promising activity against TNBC. Citation Format: Gabrielle Vontz, Jun Li, Zhipin Liang, Ruixia Ma, Pingyuan Wang, Haiying Chen, Jia Zhou, Qiang Shen. Oridonin derivative compounds target STATs to inhibit triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3328.