Department of Molecular Biology, Ariel University, Ariel 40700, Israel.
Department of Chemical Engineering, Ariel University, Ariel 40700, Israel.
Cells. 2022 Nov 18;11(22):3671. doi: 10.3390/cells11223671.
Finding synergistic drug combinations is an important area of cancer research. Here, we sought to rationally design synergistic drug combinations with an inhibitor of BTK kinase, ibrutinib, which is used for the treatment of several types of leukemia. We (a) used a pooled shRNA screen to identify genes that protect cells from the drug, (b) identified protective pathways via bioinformatics analysis of these gene sets, and (c) identified drugs that inhibit these pathways. Based on this analysis, we established that inhibitors of proteasome and mTORC1 could synergize with ibrutinib both in vitro and in vivo. We suggest that FDA-approved inhibitors of these pathways could be effectively combined with ibrutinib for the treatment of chronic lymphocytic leukemia (CLL).
寻找协同药物组合是癌症研究的一个重要领域。在这里，我们试图通过设计一种与 BTK 激酶抑制剂伊布替尼（用于治疗多种类型白血病）协同作用的药物组合来实现这一目标。我们（a）使用汇集的 shRNA 筛选来鉴定可以保护细胞免受药物侵害的基因，（b）通过对这些基因集的生物信息学分析来鉴定保护途径，以及（c）鉴定抑制这些途径的药物。基于此分析，我们确定蛋白酶体和 mTORC1 的抑制剂可以在体外和体内与伊布替尼协同作用。我们建议，可以将这些途径的 FDA 批准抑制剂与伊布替尼有效结合，用于治疗慢性淋巴细胞白血病（CLL）。
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