Inhibition of the CDK4/6-Cyclin D-Rb Pathway by Ribociclib Augments Chemotherapy and Immunotherapy in Renal Cell Carcinoma
Inhibition of the CDK4/6-Cyclin D-Rb Pathway by Ribociclib Augments Chemotherapy and Immunotherapy in Renal Cell Carcinoma
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DOI：
10.1155/2020/9525207
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发表时间：
2020-06-12
影响因子：
--
通讯作者：
Cao, Jun
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文献类型：
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作者：
Chen, Dehong;Sun, Xiaosong;Cao, Jun
肾细胞癌（RCC）是泌尿生殖系统癌症中最具侵袭性的一种，对目前的治疗方法具有耐药性。鉴别能在亚致死浓度下增强RCC标准治疗药物疗效的药物是一种替代治疗策略。Ribociclib是一种口服周期蛋白依赖性激酶4和6 （CDK4/6）抑制剂，已被批准用于治疗乳腺癌。在这项工作中，我们证明了在临床可达到的浓度下，核糖环尼可抑制9种RCC细胞系中的7种的增殖，其IC（50）范围为76至280 nM。此外，核糖环尼可诱导RCC细胞凋亡，但与其抗增殖活性相比，其效力较弱。核糖素与化疗或免疫治疗药物联合使用对RCC细胞系具有协同作用。值得注意的是，ribociclib通过保留正常肾细胞和成纤维细胞显示出选择性抗rcc活性。与他们的体外研究结果一致，在不导致小鼠毒性的剂量下，ribociclib抑制了RCC的生长，并增强了RCC标准治疗药物的体内疗效。在机制上，我们发现ribociclib显著抑制视网膜母细胞瘤蛋白（Rb）在不同位点的磷酸化，从而抑制RCC细胞中E2F靶基因的转录。我们的研究结果通过抑制CDK4/6-cyclin D/Rb通路，清楚地证明了ribociclib在RCC临床前模型中的效力和选择性。我们的研究结果支持在RCC中联合使用核糖环尼与化疗/免疫治疗的临床试验。
Renal cell carcinoma (RCC) is the most aggressive type of genitourinary cancer and is resistant to current therapies. Identifying drugs that enhance the efficacy of RCC standard-of-care drugs at sublethal concentrations is an alternative therapeutic strategy. Ribociclib is an orally available cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is approved for the treatment of breast cancer. In this work, we demonstrate that ribociclib at clinically achievable concentrations inhibits proliferation of 7 out of 9 tested RCC cell lines, with IC(50)range from 76 to 280 nM. In addition, ribociclib induces apoptosis of RCC cells, but with less potency compared to its antiproliferative activity. The combination of ribociclib with chemotherapeutic or immunotherapeutic agents is synergistic in RCC cell lines. Of note, ribociclib demonstrates selective anti-RCC activity by sparing normal kidney cells and fibroblast cells. Consistent with thein vitrofindings, ribociclib inhibits RCC growth at the dosage that does not lead to toxicity in mice and enhances thein vivoefficacy of RCC standard-of-care drugs. Mechanistically, we show that ribociclib remarkably inhibits phosphorylation of retinoblastoma protein (Rb) at various sites, leading to the suppression of transcription of E2F target genes in RCC cells. Our findings clearly demonstrate the potency and selectivity of ribociclib in RCC preclinical models, via inhibition of the CDK4/6-cyclin D/Rb pathway. Our findings support a clinical trial for the combination of ribociclib with chemo/immunotherapy in RCC.