Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Bone Tumor Institution, Shanghai 201620, China.
Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
EBioMedicine. 2018 May;31:276-286. doi: 10.1016/j.ebiom.2018.05.003.
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.
组蛋白去乙酰化酶抑制剂 (HDACi) 是一种针对表观遗传酶的小分子药物，已被批准用于血液系统恶性肿瘤，并且在实体肿瘤中也显示出临床活性。在我们目前的研究中，我们筛选了内部化合物库，发现了一种新型的 HDACi，即 WW437，它在体外和体内均具有很强的抗乳腺癌能力。WW437 可显著抑制磷酸化 EphA2 和 EphA2 的表达。进一步的研究表明，WW437 阻断了乳腺癌中的 HDAC-EphA2 信号轴。与此同时，我们发现 EphA2 的表达与乳腺癌的进展呈正相关；并且 WW437 与 EphA2 抑制剂（ALW-II-41-27）联合使用对乳腺癌的生长抑制作用比单独使用任一药物更为显著。我们的研究结果表明，单独使用 WW437 或联合其他药物抑制 HDAC-EphA2 信号轴可能是治疗晚期乳腺癌的一种有前途的治疗策略。
