Uras Iris Z, Walter Gina J, Scheicher Ruth, Bellutti Florian, Prchal-Murphy Michaela, Tigan Anca S, Valent Peter, Heidel Florian H, Kubicek Stefan, Scholl Claudia, Fröhling Stefan, Sexl Veronika
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany;
Blood. 2016 Jun 9;127(23):2890-902. doi: 10.1182/blood-2015-11-683581. Epub 2016 Apr 20.
Up to 30% of patients with acute myeloid leukemia have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD(+) acute myeloid leukemia; however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors.
高达30%的急性髓系白血病患者存在FLT3受体酪氨酸激酶的组成性激活内部串联重复（ITD）。此类突变与预后不良以及缓解后高复发倾向相关。FLT3抑制剂正作为FLT3-ITD（+）急性髓系白血病的靶向治疗药物进行研发；然而，其应用因耐药性的快速产生而变得复杂，这表明需要其他治疗靶点。我们发现，美国食品药品监督管理局批准的CDK4/6激酶抑制剂帕博西尼可诱导FLT3-ITD白血病细胞凋亡。该效应对FLT3突变细胞具有特异性，且归因于CDK6的转录活性：在FLT3和PIM1基因（另一个重要的白血病致癌驱动因子）的启动子处发现了CDK6而非其功能同源物CDK4。在那里，CDK6以激酶依赖性方式调节转录。具有潜在临床相关性的是，帕博西尼与FLT3抑制剂联合治疗可产生协同细胞毒性。同时靶向白血病发生中的两个关键信号节点可能代表一种治疗突破，从而实现完全缓解并克服对FLT3抑制剂的耐药性。
