FMS-like tyrosine kinase 3 (FLT3) is a crucial regulator of normal hematopoiesis, with high expression in hematopoietic stem and progenitor cells. Beyond its role in stem cell survival and proliferation, FLT3 signaling is essential for immune regulation, particularly dendritic cell differentiation and NK cell expansion. In acute myeloid leukemia (AML), FLT3 mutations—most commonly internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) substitutions—are among the most frequent genetic alterations, driving constitutive activation of proliferative and antiapoptotic pathways and conferring adverse prognosis. The clinical development of FLT3 inhibitors has been a decades-long endeavor. Early multikinase agents established proof-of-concept but were hampered by off-target effects and incomplete efficacy. The subsequent generation of potent and selective inhibitors has transformed outcomes, culminating in FDA approvals of midostaurin, quizartinib, and gilteritinib. Together with allogeneic transplantation, these agents have reshaped the treatment paradigm for FLT3-mutant AML, converting a historically high-risk subset into one with realistic prospects for long-term survival. Despite these advances, challenges remain. Resistance emerges through cell-intrinsic mechanisms such as acquisition of secondary TKD or RAS pathway mutations, metabolic reprogramming, and antiapoptotic shifts, as well as cell-extrinsic mechanisms mediated by the bone marrow microenvironment, including cytokine support, stromal CYP3A4 metabolism, and retinoid inactivation. These pathways sustain measurable residual disease (MRD), the key predictor of relapse. Rational combination strategies and MRD-directed approaches are therefore essential to fully realize the curative potential of FLT3 inhibition.
FMS样酪氨酸激酶3（FLT3）是正常造血过程的关键调控因子，在造血干细胞和祖细胞中高表达。除维持干细胞存活与增殖外，FLT3信号通路对免疫调节至关重要，尤其影响树突状细胞分化和自然杀伤细胞扩增。在急性髓系白血病（AML）中，FLT3突变——最常见为内部串联重复（FLT3-ITD）和酪氨酸激酶结构域（FLT3-TKD）替换——属于最高发的遗传学改变，驱动增殖与抗凋亡通路的持续激活，导致不良预后。 FLT3抑制剂的临床研发历经数十年探索。早期多激酶抑制剂验证了治疗概念，但受限于脱靶效应和疗效不足。后续强效选择性抑制剂的出现彻底改变了治疗格局，米哚妥林、奎扎替尼和吉瑞替尼相继获得FDA批准。这些药物与异基因造血干细胞移植共同重塑了FLT3突变AML的治疗范式，使这一传统高危亚型患者获得长期生存的现实可能。 尽管取得重大进展，治疗挑战依然存在。耐药机制包括细胞内在因素（如继发性TKD突变、RAS通路突变、代谢重编程和抗凋亡通路激活）以及骨髓微环境介导的细胞外在因素（如细胞因子支持、基质细胞CYP3A4代谢和维甲酸失活）。这些通路维持着可测量残留病（MRD）——AML复发的关键预测指标。因此，合理的联合治疗策略与MRD导向的治疗方案对于充分实现FLT3抑制剂的治愈潜力至关重要。
FLT3: A 35-Year Voyage from Discovery to the Next Generation of Targeted Therapy in AML
肿瘤(癌症)患者之家