Abstract 423: β-Escin eradicates cancer stem-like population in HER2-positive breast cancer with trastuzumab resistance

Abstract Purpose: Trastuzumab resistance is a multifactorial phenomenon arising from the steric effects of p95HER2, activation of HER2 downstream signaling pathways, and the existence of cancer stem cells. We sought to examine the capacity of β-escin, an anti-inflammatory drug, to address trastuzumab resistance in HER2-positive breast cancer cells. Experimental designs: The effects of β-escin in trastuzumab-sensitive and -resistant cell lines were evaluated for apoptosis, HER2 expression, calpain activation and CSC-like properties. In vivo trastuzumab-resistant xenograft mice model was used to examine tumor growth, angiogenesis and organ toxicity of β-escin. Results: β-escin induced mitochondrial-mediated apoptosis accompanied by reactive oxygen species (ROS) production and increased active p18Bax fragmentation, leading to caspase-3/-7 activation. β-escin downregulated p95HER2, HER2 and HER3 as well as their phosphorylation. β-escin-induced HER2 degradation appears to be mediated by calpain activation. We observed that treatment with β-escin induced cleavage of HER2 and p95HER2 (at 75, 50 and 42 kDa fragments) in HER2 overexpressing MDA-MB-231 cells. Attenuation of CSC-related features by β-escin challenge was accompanied by marked reductions in CD44high/CD24low stem-like cells and aldehyde dehydrogenase 1 (ALDH1) activity as well as hindrance of mammosphere formation. β-escin administration also significantly retarded tumor growth and angiogenesis in a trastuzumab-resistant JIMT-1 xenograft model via downregulation of CSC-associated markers and intracellular domain HER2. Importantly, β-escin selectively inhibited malignant cells and was less toxic to normal mammary cells, and no toxic effects were found in liver and kidney function in animals. Conclusion: Herein, for the first time, we report the potent efficacy of β-escin, a drug repurposing candidate with an exceptional safety profile in addressing trastuzumab-resistant HER2-positive breast cancer. Citation Format: Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Eunsun Jung, Yong koo Kang, Seojin Jang, So Ra Seock, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Jaeyoun Park. β-Escin eradicates cancer stem-like population in HER2-positive breast cancer with trastuzumab resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 423.