Department of Hematology/Oncology, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
Blood. 2010 Dec 9;116(24):5089-102. doi: 10.1182/blood-2010-04-261867. Epub 2010 Aug 12.
Mutations within the FMS-like tyrosine kinase 3 (FLT3) gene on chromosome 13q12 have been detected in up to 35% of acute myeloid leukemia (AML) patients and represent one of the most frequently identified genetic alterations in AML. Over the last years, FLT3 has emerged as a promising molecular target in therapy of AML. Here, we review results of clinical trials and of correlative laboratory studies using small molecule FLT3 tyrosine kinase inhibitors (TKIs) in AML patients. We also review mechanisms of primary and secondary drug resistance to FLT3-TKI, and from the data currently available we summarize lessons learned from FLT3-TKI monotherapy. Finally, for using FLT3 as a molecular target, we discuss novel strategies to overcome treatment failure and to improve FLT3 inhibitor therapy.
在多达 35%的急性髓系白血病 (AML) 患者中，已检测到位于 13q12 染色体上的 FMS 样酪氨酸激酶 3 (FLT3) 基因突变，这是 AML 中最常发现的遗传改变之一。近年来，FLT3 已成为 AML 治疗中很有前途的分子靶点。在此，我们综述了使用小分子 FLT3 酪氨酸激酶抑制剂 (TKI) 的临床试验和相关实验室研究的结果。我们还综述了 AML 患者对 FLT3-TKI 出现原发性和继发性耐药的机制，根据目前可获得的数据，我们总结了从 FLT3-TKI 单药治疗中获得的经验教训。最后，为了将 FLT3 作为一个分子靶点，我们讨论了克服治疗失败和改善 FLT3 抑制剂治疗的新策略。
