CDK4/6 inhibition as maintenance and combination therapy for high grade serous ovarian cancer.
CDK4/6 inhibition as maintenance and combination therapy for high grade serous ovarian cancer.
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DOI：
10.18632/oncotarget.24585
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发表时间：
2018-03-20
期刊：
影响因子：
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通讯作者：
Buckanovich RJ
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文献类型：
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作者：
Iyengar M;O'Hayer P;Cole A;Sebastian T;Yang K;Coffman L;Buckanovich RJ
高级别浆液性卵巢癌（HGSOC）是一种复发率高、总生存率低的疾病，尽管对铂类药物治疗的初始反应良好。靶向CDK 4/6抑制剂的细胞周期抑制是一种新的治疗方法，有望作为癌症的维持治疗。由于CDK 4/6通路中的多个基因在卵巢癌中通常发生突变或失调，我们评估了CDK 4/6抑制剂Ribociclib单独使用、与化疗联合使用以及作为维持治疗在几种HGSOC模型中的疗效。Ribociclib在多种卵巢癌细胞系中抑制细胞增殖。限制性增殖与假衰老细胞表型相关; Ribociclib处理的细胞表达衰老标志物，但可以在停止治疗后迅速重新进入细胞周期。令人惊讶的是，Ribociclib和顺铂同时治疗后，Ribociclib维持治疗具有协同作用。对细胞周期的评估表明，Ribociclib也可能通过ATR和CHK 1的去磷酸化作用于G2/M检查点。与这一机制一致，Ribociclib在体内铂类耐药和铂类敏感肿瘤模型中均表现出明显的活性。这项工作支持使用Ribociclib联合顺铂作为卵巢癌维持治疗的临床试验。
High grade serous ovarian cancer (HGSOC) is a disease with a high relapse rate and poor overall survival despite good initial responses to platinum-based therapy. Cell cycle inhibition with targeted CDK4/6 inhibitors is a new therapeutic approach showing promise as a maintenance therapy in cancer. As multiple genes in the CDK4/6 pathway are commonly mutated or dysregulated in ovarian cancer, we evaluated the efficacy of the CDK4/6 inhibitor Ribociclib alone, in combination with chemotherapy, and as maintenance therapy in several models of HGSOC. Ribociclib restricted cellular proliferation in multiple ovarian cancer cell lines. Restricted proliferation was associated with a pseudo-senescent cellular phenotype; Ribociclib-treated cells expressed markers of senescence, but could rapidly re-enter the cell cycle with discontinuation of therapy. Surprisingly, concurrent Ribociclib and cisplatin therapy followed by Ribociclib maintenance was synergistic. Evaluation of the cell cycle suggested that Ribociclib may also act at the G2/M check point via dephosphorylation of ATR and CHK1. Consistent with this mechanism, Ribociclib demonstrated clear activity in both platinum-resistant and platinum-sensitive tumor models in vivo. This work supports clinical trials using Ribociclib in combination with cisplatin and as a maintenance therapy in ovarian cancer.