CDK6 protects epithelial ovarian cancer from platinum-induced death via FOXO3 regulation.
CDK6 protects epithelial ovarian cancer from platinum-induced death via FOXO3 regulation.
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DOI：
10.15252/emmm.201607012
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发表时间：
2017-10
影响因子：
11.1
通讯作者：
Baldassarre G
中科院分区：
文献类型：
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作者：
Dall'Acqua A;Sonego M;Pellizzari I;Pellarin I;Canzonieri V;D'Andrea S;Benevol S;Sorio R;Giorda G;Califano D;Bagnoli M;Militello L;Mezzanzanica D;Chiappetta G;Armenia J;Belletti B;Schiappacassi M;Baldassarre G
上皮性卵巢癌（EOC）是一种罕见但高致死性的疾病，几乎总是采用铂类药物治疗。改善对铂的反应是一个巨大的挑战，因为它可能会显着影响患者的生存。在这里，我们报告沉默或药理学抑制CDK 6增加EOC细胞对铂的敏感性。我们观察到，在铂处理后，CDK 6磷酸化并稳定转录因子FOXO 3，最终诱导ATR转录。这一途径的阻断导致EOC细胞死亡，这是由于DNA损伤反应的改变伴随着细胞凋亡的增加。这些观察结果在体外EOC细胞系、体内异种移植物和铂治疗患者的原发性肿瘤细胞中得到了重现。一致地，原发性EOC中CDK 6和FOXO 3的高表达水平预示患者生存率差。我们的数据表明，CDK 6是一个可操作的靶点，可用于改善EOC患者的铂类疗效。随着CDK 4/6抑制剂在癌症患者中的成功应用，我们的研究结果可以立即转移到临床，以改善EOC患者的预后。
Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum‐based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro, in xenografts in vivo, and in primary tumor cells derived from platinum‐treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients.