Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
Blood. 2012 Nov 15;120(20):4205-14. doi: 10.1182/blood-2012-01-402545. Epub 2012 Sep 25.
A hallmark of cancer is the disruption of differentiation within tumor cells. Internal tandem duplication mutations of the FLT3 kinase (FLT3/ITD) occur commonly in acute myeloid leukemia (AML) and are associated with poor survival, leading to efforts to develop FLT3 kinase inhibitors. However, FLT3 inhibitors have thus far met with limited success, inducing only a clearance of peripheral blasts with minimal BM responses. Quizartinib is a novel potent and selective FLT3 inhibitor currently being studied in clinical trials. In 13 of 14 FLT3/ITD AML patients with normal karyotype treated with quizartinib, we observed terminal myeloid differentiation of BM blasts in association with a clinical differentiation syndrome. The single patient whose blasts failed to differentiate had a preexisting C/EBPα mutation and another developed a C/EBPα mutation at disease progression, suggesting a mechanism of resistance to FLT3 inhibition. In vitro, in primary blasts cocultured with human BM stroma, FLT3 inhibition with quizartinib induced cell-cycle arrest and differentiation rather than apoptosis. The present study is the first description of terminal differentiation of cancer cells in patients treated with a tyrosine kinase inhibitor. These data highlight the importance of the differentiation block in the patho-genesis of AML.
癌症的一个标志是肿瘤细胞内分化的中断。FLT3 激酶（FLT3/ITD）的内部串联重复突变在急性髓系白血病（AML）中很常见，与不良预后相关，导致人们努力开发 FLT3 激酶抑制剂。然而，到目前为止，FLT3 抑制剂的应用效果有限，仅能清除外周blasts，对骨髓反应的影响很小。Quizartinib 是一种新型强效和选择性的 FLT3 抑制剂，目前正在临床试验中进行研究。在 14 例核型正常的携带 FLT3/ITD 的 AML 患者中，我们观察到quizartinib 治疗后 BMblasts 出现终末髓系分化，并伴有临床分化综合征。唯一未能分化的患者存在预先存在的 C/EBPα 突变，另一名患者在疾病进展时发生了 C/EBPα 突变，提示对 FLT3 抑制有耐药机制。在体外，与人类 BM 基质共培养的原代blasts 中，quizartinib 抑制 FLT3 诱导细胞周期停滞和分化，而不是凋亡。本研究首次描述了接受酪氨酸激酶抑制剂治疗的患者中癌细胞的终末分化。这些数据强调了分化阻滞在 AML 发病机制中的重要性。
