Clinical studies have shown that subsets of patients with cancer achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain helicase DNA binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. Pan-cancer drug sensitivity analyses revealed that high expression of CHD1 was associated with increased sensitivity to Aurora kinase A (AURKA) inhibitors. Mechanistically, KPNA2 served as a direct target of CHD1 and suppressed the interaction of AURKA with the coactivator TPX2, thereby rendering cancer cells more vulnerable to AURKA inhibitors. Consistent with previous research reporting that loss of PTEN elevates CHD1 levels, studies in a genetically engineered mouse model, patient-derived organoids, and patient samples showed that PTEN defects are associated with a better response to AURKA inhibition in advanced prostate cancer. These observations demonstrate that CHD1 plays an important role in modulating Aurora kinases and drug sensitivities, providing new insights into biomarker-driven therapies targeting Aurora kinases for future clinical studies. Significance: CHD1 plays a critical role in controlling AURKA activation and promoting Aurora kinase inhibitor sensitivity, providing a potential clinical biomarker to guide cancer treatment.

中文翻译：

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CHD1 通过抑制 AURKA 与其共激活剂 TPX2 的相互作用来提高对极光激酶抑制剂的敏感性

临床研究表明，部分癌症患者从极光激酶抑制剂中获得了显着的益处，这表明迫切需要确定用于预测药物反应的生物标志物。染色质结构域解旋酶 DNA 结合蛋白 1 (CHD1) 参与染色质重塑、DNA 修复和转录可塑性。先前的研究表明，CHD1 在具有不同分子特征的癌症中具有不同的表达模式，但其对药物反应性的影响仍未得到充分研究。在这里，我们发现 CHD1 促进前列腺癌细胞对针对 Aurora 激酶的抑制剂的敏感性，而 CHD1 的耗竭会损害其体外和体内功效。泛癌药物敏感性分析显示，CHD1 的高表达与极光激酶 A (AURKA) 抑制剂的敏感性增加相关。从机制上讲，KPNA2 作为 CHD1 的直接靶标，抑制 AURKA 与共激活剂 TPX2 的相互作用，从而使癌细胞更容易受到 AURKA 抑制剂的影响。与之前报道的 PTEN 缺失会升高 CHD1 水平的研究一致，对基因工程小鼠模型、患者来源的类器官和患者样本的研究表明，PTEN 缺陷与晚期前列腺癌中对 AURKA 抑制的更好反应相关。这些观察结果表明，CHD1 在调节 Aurora 激酶和药物敏感性方面发挥着重要作用，为未来的临床研究提供了针对 Aurora 激酶的生物标志物驱动疗法的新见解。意义：CHD1 在控制 AURKA 激活和促进​​极光激酶抑制剂敏感性方面发挥着关键作用，