Inhibition of HDACs-EphA2 Signaling Axis with WW437 Demonstrates Promising Preclinical Antitumor Activity in Breast Cancer

Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs-EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer.
Highlights • WW437 is a novel HDACi, which displays potent anticancer activity in breast cancer. • HDACs-EphA2 signaling axis represents a novel target in breast cancer. • WW437 is a promising therapeutic agent for advanced breast cancer, alone or in combination with EphA2 inhibitor. Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL) and multiple myeloma (MM) treatment, which have also demonstrated clinical activities in solid tumors, including lung cancer and breast cancer. Herein we report a novel HDACi WW437, which displays potent anticancer activity in both cultured cancer cells and xenograft models. Importantly, our work reveals WW437 significantly blocked the HDACs-EphA2 signaling axis in breast cancer. WW437 exhibited significant inhibitory effects on tumor growth and metastases with little toxicity, and tumors from treated mice showed decreased EphA2 expression, suggesting that EphA2 may be a useful biomarker of response to WW437. We also found that EphA2 expression positively correlates with tumor progression in aggressive breast cancer.