Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Leuk Res. 2012 Feb;36(2):224-31. doi: 10.1016/j.leukres.2011.07.011. Epub 2011 Jul 29.
Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) mutation have a poor prognosis, and FLT3 inhibitors are now under clinical investigation. PIM1, a serine/threonine kinase, is up-regulated in FLT3-ITD AML and may be involved in FLT3-mediated leukemogenesis. We employed a PIM1 inhibitor, AR00459339 (Array Biopharma Inc.), to investigate the effect of PIM1 inhibition in FLT3-mutant AML. Like FLT3 inhibitors, AR00459339 was preferentially cytotoxic to FLT3-ITD cells, as demonstrated in the MV4-11, Molm-14, and TF/ITD cell lines, as well as 12 FLT3-ITD primary samples. Unlike FLT3 inhibitors, AR00459339 did not suppress phosphorylation of FLT3, but did promote the de-phosphorylation of downstream FLT3 targets, STAT5, AKT, and BAD. Combining AR00459339 with a FLT3 inhibitor resulted in additive to mildly synergistic cytotoxic effects. AR00459339 was cytotoxic to FLT3-ITD samples from patients with secondary resistance to FLT3 inhibitors, suggesting a novel benefit to combining these agents. We conclude that PIM1 appears to be closely associated with FLT3 signaling, and that inhibition of PIM1 may hold therapeutic promise, either as monotherapy, or by overcoming resistance to FLT3 inhibitors.
急性髓系白血病（AML）伴有 FLT3 内部串联重复（ITD）突变的患者预后较差，目前 FLT3 抑制剂正在临床研究中。丝氨酸/苏氨酸激酶 PIM1 在 FLT3-ITD AML 中上调，可能参与 FLT3 介导的白血病发生。我们使用 PIM1 抑制剂 AR00459339（Array Biopharma Inc.）来研究 PIM1 抑制在 FLT3 突变 AML 中的作用。与 FLT3 抑制剂一样，AR00459339对 FLT3-ITD 细胞具有优先的细胞毒性，在 MV4-11、Molm-14 和 TF/ITD 细胞系以及 12 个 FLT3-ITD 原发性样本中得到证实。与 FLT3 抑制剂不同，AR00459339 不抑制 FLT3 的磷酸化，但确实促进了下游 FLT3 靶标 STAT5、AKT 和 BAD 的去磷酸化。将 AR00459339 与 FLT3 抑制剂联合使用可产生相加至轻度协同的细胞毒性作用。AR00459339 对 FLT3 抑制剂继发耐药的患者的 FLT3-ITD 样本具有细胞毒性，表明联合使用这些药物具有新的益处。我们得出结论，PIM1 似乎与 FLT3 信号密切相关，抑制 PIM1 可能具有治疗潜力，无论是作为单一疗法，还是通过克服对 FLT3 抑制剂的耐药性。
