Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
National Institute of Animal Biotechnology, Hyderabad 500029, India.
Int J Mol Sci. 2023 Feb 15;24(4):3915. doi: 10.3390/ijms24043915.
EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics. Our screen identified the Wee1 kinase inhibitor, MK1775, as a synergistic partner to EphA2, and this finding was confirmed using both in vitro and in vivo experiments. We hypothesized that Wee1 inhibition would sensitize cells to EphA2-targeted therapy. Combination treatment decreased cell viability, induced apoptosis, and reduced clonogenic potential in endometrial cancer cell lines. In vivo Hec1A and Ishikawa-Luc orthotopic mouse models of endometrial cancer showed greater anti-tumor responses to combination treatment than to either monotherapy. RNASeq analysis highlighted reduced cell proliferation and defective DNA damage response pathways as potential mediators of the combination's effects. In conclusion, our preclinical findings indicate that Wee1 inhibition can enhance the response to EphA2-targeted therapeutics in endometrial cancer; this strategy thus warrants further development.
EphA2 酪氨酸激酶在许多癌症中上调，并与包括子宫内膜癌患者在内的患者的不良预后相关。针对 EphA2 的药物已显示出适度的临床获益。为了提高对这些药物的治疗反应，我们进行了高通量化学筛选，以发现 EphA2 靶向治疗的新协同伙伴。我们的筛选发现 Wee1 激酶抑制剂 MK1775 是 EphA2 的协同伙伴，这一发现通过体外和体内实验得到了证实。我们假设 Wee1 抑制会使细胞对 EphA2 靶向治疗敏感。联合治疗降低了子宫内膜癌细胞系的细胞活力，诱导了细胞凋亡，并降低了克隆形成能力。在体内 Hec1A 和 Ishikawa-Luc 同源性子宫内膜癌小鼠模型中，与单药治疗相比，联合治疗显示出更强的抗肿瘤反应。RNAseq 分析突出了降低的细胞增殖和有缺陷的 DNA 损伤反应途径作为组合作用的潜在介导物。总之，我们的临床前研究结果表明，Wee1 抑制可以增强 EphA2 靶向治疗在子宫内膜癌中的反应；因此，这种策略值得进一步开发。
