Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2022 Sep 2;82(17):3088-3101. doi: 10.1158/0008-5472.CAN-22-0631.
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.
CHD1 plays a critical role in controlling AURKA activation and promoting Aurora kinase inhibitor sensitivity, providing a potential clinical biomarker to guide cancer treatment.
临床研究表明，癌症患者亚群从 Aurora 激酶抑制剂中获得显著益处，这表明迫切需要确定预测药物反应的生物标志物。染色质螺旋酶 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，但它对药物反应性的影响仍未得到充分研究。在这里，我们表明 CHD1 促进了前列腺癌细胞对靶向 Aurora 激酶的抑制剂的敏感性，而 CHD1 的耗竭则会损害它们在体外和体内的疗效。泛癌症药物敏感性分析显示，CHD1 的高表达与对 Aurora 激酶 A（AURKA）抑制剂的敏感性增加有关。从机制上讲，KPNA2 是 CHD1 的直接靶标，并抑制了 AURKA 与共激活因子 TPX2 的相互作用，从而使癌细胞对 AURKA 抑制剂更敏感。与先前研究报告指出缺失 PTEN 会升高 CHD1 水平一致，在基因工程小鼠模型、患者来源的类器官和患者样本中的研究表明，PTEN 缺陷与晚期前列腺癌中对 AURKA 抑制的反应更好有关。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靶向 Aurora 激酶的生物标志物驱动治疗的新见解。
CHD1 在控制 AURKA 激活和促进 Aurora 激酶抑制剂敏感性方面发挥着关键作用，为指导癌症治疗提供了一个潜在的临床生物标志物。
