Platinum-based chemotherapy has been the standard treatment for ovarian cancer patients for approximately four decades. However, the prognosis of patients with advanced ovarian carcinoma remains dismal, mainly attributed to both dose-limiting toxicities of cisplatin and the high rate of chemo-resistant disease recurrence. Herein, both patient-derived and experimentally generated cisplatin-sensitive and -resistant ovarian cancer cell line models were used to delineate BADSer99 phosphorylation as an actionable target in ovarian cancer. BADSer99 phosphorylation was negatively associated with cisplatin sensitivity in ovarian cancer, and the inhibition of BADSer99 phosphorylation by point mutation induced apoptosis and reduced cisplatin IC₅₀. In addition, BAD phosphorylation was also shown to be associated with cancer stem cell-like properties. Henceforth, a novel small molecule which inhibits BAD phosphorylation specifically at Ser99 (NPB) was utilized. NPB promoted apoptosis and reduced 3D growth of bulk cancer cells and inhibited cancer stem cell-like properties in both cisplatin-sensitive and -resistant ovarian cancer cells. The combination of cisplatin with NPB exhibited synergistic effects in vitro. NPB in combination with cisplatin also achieved an improved outcome compared to either monotreatment in vivo, including suppression of the cancer stem cell population, an effect not observed with cisplatin treatment. Furthermore, NPB exhibited strong synergistic effects with the AKT inhibitor AZD5363, and significantly reduced its IC₅₀ in cells resistant to cisplatin treatment. These findings identify BADSer99 phosphorylation as an actionable and pharmacologically relevant target to improve outcomes of cisplatin treated ovarian cancer.

中文翻译：

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BAD Ser99 磷酸化的药理学抑制通过抑制癌症干细胞样行为增强顺铂在卵巢癌中的疗效

以铂为基础的化疗已成为卵巢癌患者的标准治疗方法，已有近四年的历史。然而，晚期卵巢癌患者的预后仍然不佳，主要归因于顺铂的剂量限制性毒性和化疗耐药性疾病的高复发率。在本文中，患者来源和实验生成的顺铂敏感和耐药卵巢癌细胞系模型均用于描述 BADSer99 磷酸化作为卵巢癌中的可操作靶标。BADSer99 磷酸化与卵巢癌顺铂敏感性呈负相关，通过点突变抑制 BADSer99 磷酸化可诱导细胞凋亡并降低顺铂 IC ₅₀. 此外，还显示 BAD 磷酸化与癌症干细胞样特性有关。此后，使用了一种新的小分子，它可以特异性地抑制 Ser99 (NPB) 上的 BAD 磷酸化。NPB 促进细胞凋亡并减少大量癌细胞的 3D 生长，并抑制顺铂敏感性和抗性卵巢癌细胞中的癌症干细胞样特性。顺铂与NPB的组合在体外表现出协同作用。与体内单一治疗相比，NPB 联合顺铂也取得了更好的结果，包括抑制癌症干细胞群，这是顺铂治疗未观察到的效果。此外，NPB 与 AKT 抑制剂 AZD5363 表现出强烈的协同作用，并显着降低其在对顺铂治疗有抗性的细胞中的IC ₅₀。这些发现将 BADSer99 磷酸化确定为可操作且药理学相关的靶标，以改善顺铂治疗的卵巢癌的结果。