文章：

伊布替尼和维奈托克靶向CLL细胞的不同亚群：对残留病灶清除的意义

Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication

原文发布日期：2021-02-18

DOI: 10.1038/s41408-021-00429-z

类型: Article

开放获取: 是

英文摘要：

Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients’ actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.
 

摘要翻译： 

伊布替尼可抑制布鲁顿酪氨酸激酶，而维奈托克是抗凋亡蛋白BCL2的特异性抑制剂。这两种药物作为单药治疗慢性淋巴细胞白血病均表现出高效性，联合疗法的临床试验在完全缓解率与不可检测的微小残留病发生率方面取得了显著成效。然而，该药物组合成功的实验室理论依据尚不充分。更深入地理解这两种药物的协同作用机制，将有助于开发其他合理的联合治疗策略。通过采用促进慢性淋巴细胞白血病增殖的离体模型，我们发现模拟的伊布替尼增殖反应（而非存活反应）与患者实际临床反应高度相关。重要的是，我们首次证明伊布替尼和维奈托克作用于具有不同增殖能力的不同亚群慢性淋巴细胞白血病细胞：增殖亚群对伊布替尼敏感，而静止亚群对维奈托克反应更显著。在多数情况下，这两种靶向疗法的联合应用能有效减少静止与增殖双重亚群。我们的实验室发现有助于解释多项临床观察结果，并促进对肿瘤动态的理解。此外，该增殖模型可用于筛选具有清除残留病灶潜力的新型药物组合。

原文链接：

Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication