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首页> 外文期刊>Cell cycle >RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents.
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RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents.

机译：RB状态决定了对细胞毒性和分子靶向治疗剂的敏感性差异。

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The retinoblastoma tumor suppressor (RB) is frequently inactivated in human cancers and has been shown to modulate the anti-proliferative effects of DNA-damaging therapies. However, the impact of RB loss on response to disparately functioning cytotoxic agents as well as targeted therapies is poorly understood. Here 3T3-immortalized and Ras-transformed mouse adult fibroblasts (MAFs) containing conditional RB alleles were utilized to investigate the consequence of RB loss on cellular response to cytotoxic agents and therapies targeting the MEK and PI3K pathways. Using these models, we demonstrate that RB deficiency is associated with bypass of therapy-induced checkpoints in response to both cytotoxic and targeted treatments. Interestingly, while checkpoint bypass following treatment with cytotoxic therapy results in an agent specific increase in drug sensitivity, checkpoint bypass following treatment targeting MEK and PI3K function results in increased cellular proliferation. These results indicate that RB status differentially impacts therapeutic response and should be considered when evaluating the efficacy of molecularly targeted therapeutics.
机译：视网膜母细胞瘤抑癌剂（RB）在人类癌症中经常被灭活，并且已被证明可调节DNA破坏疗法的抗增殖作用。但是，RB丢失对功能不同的细胞毒剂以及靶向治疗反应的影响知之甚少。在这里，使用包含条件性RB等位基因的3T3永生化和Ras转化的小鼠成年成纤维细胞（MAF），来研究RB丢失对细胞对细胞毒性剂的反应以及针对MEK和PI3K途径的疗法的后果。使用这些模型，我们证明RB缺乏与对细胞毒性和靶向治疗的治疗诱导的检查点的绕过相关。有趣的是，虽然细胞毒性疗法治疗后的检查点旁路导致药物敏感性的特异性增加，而靶向MEK和PI3K功能的治疗后的检查点旁路导致细胞增殖的增加。这些结果表明，RB状态对治疗反应的影响不同，在评估分子靶向治疗剂的疗效时应予以考虑。

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