Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer
Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer
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DOI：
10.1038/s41388-019-0708-7
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发表时间：
2019-05-23
期刊：
影响因子：
8
通讯作者：
Wei, Ping
中科院分区：
文献类型：
--
作者：
Cao, Joan;Zhu, Zhou;Wei, Ping
CDK 4/6抑制剂palbociclib通过降低视网膜母细胞瘤（RB）蛋白磷酸化并诱导细胞周期停滞在G1/S期转变来减少肿瘤生长。Palbociclib联合抗激素治疗为乳腺癌患者带来显著获益。在这项研究中，在鳞状细胞肺癌（SqCLC）（第二种最常见的非小细胞肺癌亚型）中探索了Palbociclib的新型联合治疗方法和潜在的分子/细胞机制。虽然大约20%的肺部患者受益于免疫治疗，但大多数接受铂双联化疗作为一线治疗的SqCLC患者（通常包括紫杉烷）仍然需要更有效的联合治疗。我们的研究结果表明，在具有不同癌症遗传背景的多个SqCLC模型中，palbociclib联合紫杉烷类药物在临床可达到的剂量下具有增强的细胞毒性和抗肿瘤作用。综合基因表达分析揭示了通过组合持续破坏pRB-E2 F信号传导，伴随着多效性生物学效应的增强调节。这些包括几种新的机制，如废除G2/M和有丝分裂纺锤体组装检查点，以及缺氧诱导因子1 α（HIF-1 α）的诱导受损。HIF-1 α的减少调节了一对关键的血管生成和抗血管生成因子，导致增强的抗血管生成作用。这项临床前研究表明，palbociclib在肺癌和其他癌症中有新的治疗机会，这些癌症目前采用基于紫杉烷的化疗作为标准治疗。
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-1 alpha). The decrease in HIF-1 alpha 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.