晚期上皮性卵巢癌 (EOC) 的生存率低得令人沮丧，约 25% 的生存期超过 5 年。有证据表明，癌症干细胞有助于获得性化疗耐药性和肿瘤复发。在这里，我们发现 IRAK1 在 EOC 组织中表达上调，并且表达增强与较差的总体生存率相关。此外，晚期 EOC 患者的恶性腹水中富含低分子量透明质酸，可诱导 IRAK1 磷酸化，从而导致 STAT3 激活并增强球状体形成。 IRAK1 的敲低会损害腹膜疾病模型中的肿瘤生长，并损害 HA 诱导的球状体生长和 STAT3 磷酸化。最后，我们确定 TCS2210（一种已知的间充质干细胞神经元分化诱导剂）是 IRAK1 的选择性抑制剂。 TCS2210 作为单一疗法以及与顺铂联合用药均能在体外和体内显着抑制 EOC 生长。总的来说，这些数据表明 IRAK1 是 EOC 的药物靶标。© 2024。作者。

Advanced epithelial ovarian cancer (EOC) survival rates are dishearteningly low, with ~25% surviving beyond 5 years. Evidence suggests that cancer stem cells contribute to acquired chemoresistance and tumor recurrence. Here, we show that IRAK1 is upregulated in EOC tissues, and enhanced expression correlates with poorer overall survival. Moreover, low molecular weight hyaluronic acid, which is abundant in malignant ascites from patients with advanced EOC, induced IRAK1 phosphorylation leading to STAT3 activation and enhanced spheroid formation. Knockdown of IRAK1 impaired tumor growth in peritoneal disease models, and impaired HA-induced spheroid growth and STAT3 phosphorylation. Finally, we determined that TCS2210, a known inducer of neuronal differentiation in mesenchymal stem cells, is a selective inhibitor of IRAK1. TCS2210 significantly inhibited EOC growth in vitro and in vivo both as monotherapy, and in combination with cisplatin. Collectively, these data demonstrate IRAK1 as a druggable target for EOC.© 2024. The Author(s).