Ebastine impairs metastatic spread in triple-negative breast cancer by targeting focal adhesion kinase

• Published in: Cellular and molecular life sciences : CMLS Vol. 80; no. 5; p. 132
• Main Authors: Seo, Juyeon, Park, Minsu, Ko, Dongmi, Kim, Seongjae, Park, Jung Min, Park, Soeun, Nam, Kee Dal, Farrand, Lee, Yang, Jinsol, Seok, Chaok, Jung, Eunsun, Kim, Yoon-Jae, Kim, Ji Young, Seo, Jae Hong
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.05.2023; Springer Nature B.V
• Subjects: Adhesion; Angiogenesis; Antihistamines; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blood circulation; Breast cancer; CD44 antigen; Cell Biology; Cell Line, Tumor; Cell Proliferation; Extracellular signal-regulated kinase; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases; Gelatinase A; Humans; Janus kinase 2; Kinases; Life Sciences; Metastases; Metastasis; Mitogen-Activated Protein Kinase Kinases; Original; Original Article; Phosphorylation; Protein-tyrosine kinase; Stat3 protein; Stem cells; Triple Negative Breast Neoplasms - metabolism; Tumors; Tyrosine; Drug repurposing; FAK; Metastasis; Breast cancer stem cells; Ebastine; Triple-negative breast cancer
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-023-04760-5

We sought to investigate the utility of ebastine (EBA), a second-generation antihistamine with potent anti-metastatic properties, in the context of breast cancer stem cell (BCSC)-suppression in triple-negative breast cancer (TNBC). EBA binds to the tyrosine kinase domain of focal adhesion kinase (FAK), blocking phosphorylation at the Y397 and Y576/577 residues. FAK-mediated JAK2/STAT3 and MEK/ERK signaling was attenuated after EBA challenge in vitro and in vivo. EBA treatment induced apoptosis and a sharp decline in the expression of the BCSC markers ALDH1, CD44 and CD49f, suggesting that EBA targets BCSC-like cell populations while reducing tumor bulk. EBA administration significantly impeded BCSC-enriched tumor burden, angiogenesis and distant metastasis while reducing MMP-2/-9 levels in circulating blood in vivo. Our findings suggest that EBA may represent an effective therapeutic for the simultaneous targeting of JAK2/STAT3 and MEK/ERK for the treatment of molecularly heterogeneous TNBC with divergent profiles. Further investigation of EBA as an anti-metastatic agent for the treatment of TNBC is warranted.