CDK4/6抑制剂耐药机制:CDK6扩增
  • 选择性强效CDK4/6抑制剂LY2835219延长给药后,出现新的克隆,其中一些携带CDK6激酶扩增;
  • CDK6扩增导致CDK6表达明显增加、CDK4/6靶点磷酸化-Rb (pRb)对CDK4/6抑制剂的疗效下降,敲除CDK6基因,则保持了药物敏感性;
  • CDK6过表达不仅介导CDK4/6抑制剂耐药,而且下调ER和孕激素受体(PR)表达,减弱ER拮抗剂的疗效;
  • pRb缺失、细胞周期素E1过表达,也呈现激素疗效下降,后续内分泌为基础的治疗方案对某些CDK4/6获得性耐药患者可能无效。
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Oncogene [IF:7.971]

Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence

CDK6获得性扩增促进乳腺癌对CDK4/6抑制剂耐药以及ER信号传导的缺失和依赖性

10.1038/onc.2016.379

2016-06-25, Article

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Dysregulated activation of the CDK4/6 kinases is a hallmark of most mammary-derived carcinomas. ATP-competitive inhibitors against this complex have been recently advanced in the clinic and have shown significant activity, particularly against tumors driven by the estrogen receptor (ER). However, resistance to these compounds has begun to emerge often months to years after their initiation. We investigated potential mechanisms of resistance using cell line models that are highly sensitive to this class of drugs. After prolonged exposure to the selective and potent CDK4/6 inhibitor LY2835219, clones emerged and several were found to harbor amplification of the CDK6 kinase. Amplification of CDK6 resulted in a marked increase in CDK6 expression and reduced response of the CDK4/6 target, phospho-Rb (pRb), to CDK4/6 inhibitors. Knockdown of CDK6 restored drug sensitivity, while enforced overexpression of CDK6 was sufficient to mediate drug resistance. Not only did CDK6 overexpression mediate resistance to CDK4/6 inhibitors but it also led to reduced expression of the ER and progesterone receptor (PR), and diminished responsiveness to ER antagonism. The reduced ER/PR expression after CDK4/6 inhibitor resistance was additionally observed in tumor biopsy specimens from patients treated with these drugs. Alternative mechanisms of resistance to CDK4/6 inhibitors such as loss of pRb and cyclin E1 overexpression also exhibited decreased hormone responsiveness, suggesting that the clinical paradigm of sequential endocrine-based therapy may be ineffective in some settings of acquired CDK4/6 resistance.

First Authors:
C Yang, Z Li, T Bhatt

Correspondence Authors:
S Chandarlapaty

All Authors:
C Yang,Z Li,T Bhatt,M Dickler,D Giri,M Scaltriti,J Baselga,N Rosen,S Chandarlapaty

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