Weisberg Ellen, Roesel Johannes, Bold Guido, Furet Pascal, Jiang Jingrui, Cools Jan, Wright Renee D, Nelson Erik, Barrett Rosemary, Ray Arghya, Moreno Daisy, Hall-Meyers Elizabeth, Stone Richard, Galinsky Ilene, Fox Edward, Gilliland Gary, Daley John F, Lazo-Kallanian Suzan, Kung Andrew L, Griffin James D
Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA, USA.
Blood. 2008 Dec 15;112(13):5161-70. doi: 10.1182/blood-2008-02-138065. Epub 2008 Sep 26.
An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.
治疗干预的一个有吸引力的靶点是组成性激活的突变型FLT3，它在急性髓细胞白血病（AML）患者的一个亚群中表达，并且在65岁以下的患者中通常是一个不良预后指标。PKC412是正在进行临床试验的几种突变型FLT3抑制剂之一，目前处于后期临床试验阶段。然而，在接受PKC412治疗的AML患者中发现耐药性白血病母细胞，促使人们寻找结构多样的新型FLT3抑制剂，以替代使用来克服耐药性。在此，我们报告新型突变型FLT3抑制剂NVP-AST487对表达FLT3-ITD或FLT3激酶结构域点突变的原代患者细胞和细胞系具有强效且选择性的抗增殖作用。NVP-AST487选择性靶向突变型FLT3蛋白激酶活性，在体外也显示能克服PKC412耐药性，并且在FLT3-ITD(+)白血病的体内模型中具有显著的抗白血病活性。最后，NVP-AST487与标准化疗药物联合使用可增强对表达突变型FLT3细胞增殖的抑制作用。因此，我们提出了一类新型的FLT3抑制剂，其对作为分子靶点的FLT3显示出高选择性和强效性，并且有可能用于克服AML中的耐药性。
