UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models.
UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models.
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DOI：
10.1158/1078-0432.ccr-16-1330
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发表时间：
2017-03-15
期刊：
影响因子：
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通讯作者：
Graham DK
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文献类型：
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作者：
DeRyckere D;Lee-Sherick AB;Huey MG;Hill AA;Tyner JW;Jacobsen KM;Page LS;Kirkpatrick GG;Eryildiz F;Montgomery SA;Zhang W;Wang X;Frye SV;Earp HS;Graham DK
MerTK酪氨酸激酶在30-50%的急性淋巴细胞白血病(ALL)和80%以上的急性髓系白血病(AML)中异位表达，是一个潜在的治疗靶点。在这里，我们评估了MERTK酪氨酸激酶抑制剂UNC2025治疗急性白血病的有效性。使用细胞系和原代白血病患者样本进行临床前、体外和体内试验，以评估UNC2025的抗白血病作用。在表达MERTK的ALL和AML细胞系和患者样本中，Ok2025有效地抑制了促生存信号，诱导了细胞凋亡，并减少了增殖和克隆形成。大约30%的原发白血病患者样本(261个样本中的78个)对UNC2025敏感。敏感样本在AML、T-ALL和最低分化(M0)AML亚群中最常见。UNC2025抑制骨髓白血病细胞中的MERTK，并在异种移植模型中具有显著的治疗效果，无论起始疾病负担如何，肿瘤负担均呈剂量依赖性降低，中位生存期持续增加两倍。在患者来源的AML异种移植模型中，用UNC2025治疗可导致疾病消退。此外，UNC2025在体内增加了对甲氨蝶呤的敏感性，这表明在目前的细胞毒方案中增加MERTK靶向治疗可能特别有效和/或允许减少化疗剂量。UNC2025在白血病患者样本和异种移植模型中介导的广谱活性，单独或与细胞毒性化疗联合使用，支持继续开发MERTK抑制剂用于治疗白血病。
MERTK tyrosine kinase is ectopically expressed in 30–50% of acute lymphoblastic leukemias (ALL) and over 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MERTK tyrosine kinase inhibitor, for treatment of acute leukemia. Pre-clinical in vitro and in vivo assays using cell lines and primary leukemia patient samples were utilized to evaluate anti-leukemic effect of UNC2025. UNC2025 potently inhibited pro-survival signaling, induced apoptosis and reduced proliferation and colony formation in MERTK-expressing ALL and AML cell lines and patient samples. Approximately 30% of primary leukemia patient samples (78 of 261 total) were sensitive to UNC2025. Sensitive samples were most prevalent in the AML, T-ALL, and minimally differentiated (M0) AML subsets. UNC2025 inhibited MERTK in bone marrow leukemia cells and had significant therapeutic effects in xenograft models, with dose-dependent decreases in tumor burden and consistent two-fold increases in median survival, irrespective of starting disease burden. In a patient-derived AML xenograft model, treatment with UNC2025 induced disease regression. Additionally, UNC2025 increased sensitivity to methotrexate in vivo, suggesting that addition of MERTK-targeted therapy to current cytotoxic regimens may be particularly effective and/or allow for chemotherapy dose reduction. The broad spectrum activity mediated by UNC2025 in leukemia patient samples and xenograft models, alone or in combination with cytotoxic chemotherapy, support continued development of MERTK inhibitors for treatment of leukemia.