1 Department of Pathology, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
2 Center for Molecular Discovery, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
SLAS Discov. 2018 Aug;23(7):732-741. doi: 10.1177/2472555218774248. Epub 2018 May 10.
Kinase inhibitors have dramatically increased patient survival in a multitude of cancers, including hematological malignancies. However, kinase inhibitors have not yet been integrated into current clinical trials for patients with T-cell-lineage acute lymphoblastic leukemia (T-ALL). In this study, we used a high-throughput flow cytometry (HTFC) approach to test a collection of small-molecule inhibitors, including 26 FDA-approved tyrosine kinase inhibitors in a panel of T-ALL cell lines and patient-derived xenografts. Because hypoxia is known to cause resistance to chemotherapy, we developed a synthetic niche that mimics the low oxygen levels found in leukemic bone marrow to evaluate the effects of hypoxia on the tested inhibitors. Drug sensitivity screening was performed using the Agilent BioCel automated liquid handling system integrated with the HyperCyt HT flow cytometry platform, and the uptake of propidium iodide was used as an indication of cell viability. The HTFC dose-response testing identified several compounds that were efficacious in both normal and hypoxic conditions. This study shows that some clinically approved kinase inhibitors target T-ALL in the hypoxic niche of the bone marrow.
激酶抑制剂在包括血液恶性肿瘤在内的多种癌症中显著提高了患者的生存率。然而，激酶抑制剂尚未纳入 T 细胞系急性淋巴细胞白血病 (T-ALL) 患者的当前临床试验中。在这项研究中，我们使用高通量流式细胞术 (HTFC) 方法测试了一系列小分子抑制剂，包括 T-ALL 细胞系和患者来源的异种移植物中 26 种 FDA 批准的酪氨酸激酶抑制剂。由于缺氧已知会导致对化疗的耐药性，我们开发了一种合成小生境，模拟白血病骨髓中发现的低氧水平，以评估缺氧对测试抑制剂的影响。使用安捷伦 BioCel 自动化液体处理系统与 HyperCyt HT 流式细胞术平台集成进行药物敏感性筛选，碘化丙啶摄取被用作细胞活力的指示。HTFC 剂量反应测试确定了几种在正常和缺氧条件下均有效的化合物。这项研究表明，一些临床批准的激酶抑制剂在骨髓的缺氧小生境中靶向 T-ALL。
