FGF2 from Marrow Microenvironment Promotes Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia.
FGF2 from Marrow Microenvironment Promotes Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia.
复制标题
DOI：
10.1158/0008-5472.can-15-3569
复制
发表时间：
2016-11-15
期刊：
影响因子：
11.2
通讯作者：
Druker BJ
中科院分区：
文献类型：
--
作者：
Traer E;Martinez J;Javidi-Sharifi N;Agarwal A;Dunlap J;English I;Kovacsovics T;Tyner JW;Wong M;Druker BJ
高效的Flt3抑制剂如奎扎替尼(AC220)在治疗含有Flt3内部串联重复(ITD)突变的急性髓系白血病(AML)方面显示出很好的前景。然而，反应不是持久的，抗药性在几个月内就会形成。在这项研究中，我们概述了一个两步抗性模型，通过外部微环境蛋白Flt3配体(FL)和成纤维细胞生长因子2(FGF2)保护Flt3-ITD+MOLM14细胞免受AC220的影响，为后续积累配体无关的抗性机制提供时间。FL可直接减弱AC220对Flt3的抑制作用，这与以往的报道一致。相反，FGF2通过激活FGFR1和下游的MAPK效应器来促进耐药性；这些耐药细胞对FGFR1和Flt3的联合抑制做出协同反应。从配体依赖的抗性培养中去除FL或FGF2可以暂时恢复对AC220的敏感性，但通过重新激活Flt3和RAS/MAPK信号通路加速了二次抗性的获得。接受AC220治疗的Flt3-ITD AML患者骨髓基质细胞中FGF2表达增加，在临床明显复发和检测到耐药突变之前达到顶峰。总体而言，这些结果支持早期联合治疗的策略，以针对来自骨髓微环境的早期生存信号，特别是FGF2，以改善Flt3-ITD AML的反应深度。
Potent FLT3 inhibitors such as quizartinib (AC220) have shown promise in treating acute myeloid leukemia (AML) containing FLT3 internal tandem duplication (ITD) mutations. However, responses are not durable and resistance develops within months. In this study, we outline a two-step model of resistance whereby extrinsic microenvironmental proteins FLT3 ligand (FL) and fibroblast growth factor 2 (FGF2) protect FLT3-ITD+ MOLM14 cells from AC220, providing time for subsequent accumulation of ligand-independent resistance mechanisms. FL directly attenuated AC220 inhibition of FLT3, consistent with previous reports. Conversely, FGF2 promoted resistance through activation of FGFR1 and downstream MAPK effectors; these resistant cells responded synergistically to combinatorial inhibition of FGFR1 and FLT3. Removing FL or FGF2 from ligand-dependent resistant cultures transiently restored sensitivity to AC220, but accelerated acquisition of secondary resistance via reactivation of FLT3 and RAS/MAPK signaling. FLT3-ITD AML patients treated with AC220 developed increased FGF2 expression in marrow stromal cells, which peaked prior to overt clinical relapse and detection of resistance mutations. Overall, these results support a strategy of early combination therapy to target early survival signals from the bone marrow microenvironment, in particular FGF2, to improve the depth of response in FLT3-ITD AML.