High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer with few effective, targeted therapies. HGSOC tumors exhibit genomic instability with frequent alterations in the protein kinome; however, only a small fraction of the kinome has been therapeutically targeted in HGSOC. Using multiplexed inhibitor beads and mass spectrometry, we mapped the kinome landscape of HGSOC tumors from patients and patient-derived xenograft models. The data revealed a prevalent signature consisting of established HGSOC driver kinases, as well as several kinases previously unexplored in HGSOC. Loss-of-function analysis of these kinases in HGSOC cells indicated MRCKA (also known as CDC42BPA) as a putative therapeutic target. Characterization of the effects of MRCKA knockdown in established HGSOC cell lines demonstrated that MRCKA was integral to signaling that regulated the cell cycle checkpoint, focal adhesion, and actin remodeling, as well as cell migration, proliferation, and survival. Moreover, inhibition of MRCKA using the small-molecule BDP9066 decreased cell proliferation and spheroid formation and induced apoptosis in HGSOC cells, suggesting that MRCKA may be a promising therapeutic target for the treatment of HGSOC.

中文翻译：

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对蛋白质组的功能蛋白质组学研究确定MRCKA为高度浆液性卵巢癌的治疗靶标。

高度浆液性卵巢癌（HGSOC）是最致命的妇科癌症，几乎没有有效的针对性疗法。HGSOC肿瘤表现出基因组不稳定，并经常发生蛋白激酶组变化。但是，只有一小部分的激酶组在HGSOC中具有治疗目标。使用多重抑制剂珠和质谱，我们绘制了来自患者和源自患者的异种移植模型的HGSOC肿瘤的激酶组图。数据揭示了由已建立的HGSOC驱动激酶以及以前在HGSOC中未开发的几种激酶组成的普遍特征。在HGSOC细胞中对这些激酶的功能丧失分析表明，MRCKA（也称为CDC42BPA）是公认的治疗靶标。表征已建立的HGSOC细胞系中MRCKA的作用的结果表明，MRCKA是调节细胞周期检查点，粘着斑和肌动蛋白重塑以及细胞迁移，增殖和存活的信号传导所不可或缺的。此外，使用小分子BDP9066抑制MRCKA会降低HGSOC细胞的细胞增殖和球体形成并诱导细胞凋亡，这表明MRCKA可能是治疗HGSOC的有希望的治疗靶点。