Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), CMMC, Center for Molecular Medicine, University of Cologne, Germany.
Leukemia. 2018 Mar;32(3):774-787. doi: 10.1038/leu.2017.252. Epub 2017 Aug 14.
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.
T 细胞前淋巴细胞白血病（T-PLL）是一种罕见且侵袭性的成熟 T 细胞肿瘤，迫切需要合理设计的治疗方法来解决其众所周知的化疗耐药行为。T-PLL 患者的中位生存时间<2 年，临床试验难以实施。在这里，我们使用体外药物敏感性和耐药性检测平台系统地研究了 T-PLL 患者样本中药物反应的多样性，并将研究结果与体细胞突变和基因表达谱相关联。有趣的是，所有 T-PLL 样本均对细胞周期蛋白依赖性激酶抑制剂 SNS-032 敏感，该抑制剂克服了基质细胞介导的保护作用，并引起强烈的 p53 激活和凋亡。在所有患者中，最有效的化合物类别是组蛋白去乙酰化酶、磷酸肌醇 3 激酶/AKT/哺乳动物雷帕霉素靶蛋白、热休克蛋白 90 和 BH3 家族蛋白抑制剂以及 p53 激活剂，表明存在以前未知的治疗 T-PLL 的新靶向方法。尽管 JAK-STAT 途径突变在 T-PLL 中很常见（71%的患者），但 JAK-STAT 抑制剂反应与这些或其他 T-PLL 特异性病变没有直接联系。总体而言，我们发现遗传标志物不易转化为新的有效治疗弱点。总之，使用全面的体外药物筛选平台发现了 T-PLL 中具有高疗效的新型化合物类别，值得进一步研究协同作用和临床测试。
