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Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer
Oncogene ( IF 6.9 ) Pub Date : 2019-01-30 , DOI: 10.1038/s41388-019-0708-7
Joan Cao , Zhou Zhu , Hui Wang , Timothy C. Nichols , Goldie Y. L. Lui , Shibing Deng , Paul A. Rejto , Todd VanArsdale , James S. Hardwick , Scott L. Weinrich , Ping Wei

The CDK4/6 inhibitor palbociclib reduces tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Palbociclib in combination with anti-hormonal therapy brings significant benefit to breast cancer patients. In this study, novel combination approaches and underlying molecular/cellular mechanisms for palbociclib were explored in squamous cell lung cancer (SqCLC), the second most common subtype of non-small cell lung cancer. While approximate 20% lung patients benefit from immunotherapy, most SqCLC patients who receive platinum-doublet chemotherapy as first-line treatment, which often includes a taxane, are still in need of more effective combination therapies. Our results demonstrated enhanced cytotoxicity and anti-tumor effect with palbociclib plus taxanes at clinically achievable doses in multiple SqCLC models with diverse cancer genetic backgrounds. Comprehensive gene expression analysis revealed a sustained disruption of pRB-E2F signaling by combination that was accompanied with enhanced regulation of pleiotropic biological effects. These included several novel mechanisms such as abrogation of G2/M and mitotic spindle assembly checkpoints, as well as impaired induction of hypoxia-inducible factor 1 alpha (HIF-1α). The decrease in HIF-1α modulated a couple key angiogenic and anti-angiogenic factors, resulting in an enhanced anti-angiogenic effect. This preclinical work suggests a new therapeutic opportunity for palbociclib in lung and other cancers currently treated with taxane based chemotherapy as standard of care.



中文翻译:

CDK4 / 6抑制与紫杉烷类药物联合使用可通过持续损害鳞状细胞肺癌中pRB-E2F途径增强抗肿瘤功效

CDK4 / 6抑制剂palbociclib通过减少视网膜母细胞瘤(RB)蛋白磷酸化并诱导G1 / S相转变的细胞周期停滞来减少肿瘤的生长。Palbociclib与抗激素治疗相结合为乳腺癌患者带来了显着的益处。在这项研究中,palbociclib的新型组合方法和潜在的分子/细胞机制在鳞状细胞肺癌(SqCLC)(非小细胞肺癌的第二大最常见亚型)中得到了探索。尽管大约20%的肺部患者可以从免疫疗法中受益,但大多数接受铂双联化疗作为一线治疗(通常包括紫杉烷)的SqCLC患者仍需要更有效的联合疗法。我们的研究结果表明,在具有多种癌症遗传背景的多个SqCLC模型中,以临床可达到的剂量使用palbociclib加上紫杉烷类,可增强细胞毒性和抗肿瘤作用。全面的基因表达分析显示,通过联合使用,并增强了对多效性生物学效应的调节,pRB-E2F信号传导受到了持续破坏。这些包括几种新颖的机制,例如取消G2 / M和有丝分裂纺锤体装配检查点,以及缺氧诱导因子1α(HIF-1α)的诱导受损。HIF-1α的减少调节了几个关键的血管生成和抗血管生成因子,从而增强了抗血管生成作用。

更新日期:2019-01-30
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