Targeting CDK4/6 in mantle cell lymphoma.
Targeting CDK4/6 in mantle cell lymphoma.
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DOI：
10.21037/aol.2019.12.01
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发表时间：
2020-03-01
期刊：
影响因子：
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通讯作者：
Chen-Kiang, Selina
中科院分区：
文献类型：
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作者：
Lee, Christina;Huang, Xiangao;Chen-Kiang, Selina
靶向细胞周期是套细胞淋巴瘤（MCL）治疗的合理方法，因为细胞周期蛋白D1的异常表达和CDK 4的失调是MCL细胞的细胞周期进展和增殖的基础。尽管由于缺乏选择性和有效的药物，细胞周期癌症治疗在历史上是无效的，但随着选择性和有效的小分子口服CDK 4/6抑制剂的出现，这种情况发生了变化。现就CDK 4/6选择性抑制剂在MCL中的抗肿瘤活性及临床资料作一综述。我们总结了迄今为止最具特异性的CDK 4/6抑制剂palbociclib的已知作用机制，以及利用这种特异性重新编程MCL以实现对伴侣药物更深入、更持久的临床应答的策略。我们还讨论了整合纵向功能基因组学作为发现肿瘤内在基因组生物标志物和肿瘤免疫相互作用的策略，这些生物标志物和肿瘤免疫相互作用可能有助于Palbociclib在MCL联合治疗中的临床应答。了解靶向CDK 4/6的基因组基础以及MCL的作用和耐药性机制可能会促进MCL的个性化治疗，并揭示其他癌症的耐药性。
Targeting the cell cycle represents a rational approach to mantle cell lymphoma (MCL) therapy, as aberrant expression of cyclin D1 and dysregulation of CDK4 underlie cell cycle progression and proliferation of MCL cells. Although cell cycle cancer therapy was historically ineffective due to a lack of selective and effective drugs, this landscape changed with the advent of selective and potent small-molecule oral CDK4/6 inhibitors. Here, we review the anti-tumor activities and clinical data of selective CDK4/6 inhibitors in MCL. We summarize the known mechanism of action of palbociclib, the most specific CDK4/6 inhibitor to date, and the strategy to leverage this specificity to reprogram MCL for a deeper and more durable clinical response to partner drugs. We also discuss integrative longitudinal functional genomics as a strategy to discover tumor-intrinsic genomic biomarkers and tumor-immune interactions that potentially contribute to the clinical response to palbociclib in combination therapy for MCL. Understanding the genomic basis for targeting CDK4/6 and the mechanisms of action and resistance in MCL may advance personalized therapy for MCL and shed light on drug resistance in other cancers.