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单细胞转录组学揭示了与乳腺癌细胞系中CDK4/6抑制剂耐药性相关的生物标志物异质性

Ilenia Migliaccio¹, Martina Bonechi¹, Dario Romagnoli^2,3

¹Translational Research Unit, Department of Oncology, Hospital of Prato, Azienda USL Toscana Centro, Prato, Italy.

NPJ breast cancer

|July 30, 2025

概括

乳腺癌中对循环素依赖性激酶4和6抑制剂 (CDK4/6i) 的耐药性是一个挑战. 我们的研究揭示了耐药性标志物的显著异质性,影响治疗策略和生物标志物验证.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
基因组学就是基因组学.

背景情况:

循环素依赖性激酶4和6抑制剂 (CDK4/6i) 在光线乳腺癌中有效.
对CDK4/6i的治疗耐药性仍然是一个重大的临床挑战.
目前用于CDK4/6i耐药性的生物标志物缺乏临床实用性.

研究的目的:

研究光线乳腺癌中对CDK4/6抑制剂的耐药性机制的异质性.
为了确定与CDK4/6i耐药性相关的潜在转录生物标志物.
在临床试验环境中验证细胞系模型的发现.

主要方法:

单细胞RNA测序是在palbociclib-naïve和耐药的光线乳腺癌细胞系上进行的.
分析了转录资料的异质性和与药物敏感性的相关性.
使用FELINE临床试验数据验证了耐药性特征.

主要成果:

对于已确立的CDK4/6i耐药性生物标志物和途径,观察到明显的细胞内和细胞间异质性.
耐药性的转录特征存在于原始细胞中,与敏感性相关.
耐药细胞系和瘤表现出明显的转录集群,包括增殖,雌激素反应和MYC标签的变化.
在FELINE试验中,一种对MYC标增强的耐药性特征和缺乏雌激素反应标志物的耐药性特征与耐药性瘤差异化敏感,耐药性病例的异质性更大.

结论:

CDK4/6抑制剂耐药性标记物的异质性可能导致治疗失败.
观察到的异质性挑战了对CDK4/6i耐药性的单个生物标志物的临床验证.
需要进一步的研究来理解和准光线性乳腺癌的耐药性机制.

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