Institute of Pharmacology and Toxicology, University of Veterinary Medicine, 1210 Vienna, Austria.
Ludwig Boltzmann Institute for Hematology & Oncology, Medical University of Vienna, 1090 Vienna, Austria.
Int J Mol Sci. 2018 Dec 11;19(12):3987. doi: 10.3390/ijms19123987.
While significant progress has been made in the treatment of acute myeloid leukemia (AML), not all patients can be cured. Mutated in about 1/3 of de novo AML, the FLT3 receptor tyrosine kinase is an attractive target for drug development, activating mutations of the map to the juxtamembrane domain (internal tandem duplications, ITD) or the tyrosine kinase domain (TKD), most frequently at codon D835. While small molecule tyrosine kinase inhibitors (TKI) effectively target ITD mutant forms, those on the TKD are not responsive. Moreover, FLT3 inhibition fails to induce a persistent response in patients due to mutational resistance. More potent compounds with broader inhibitory effects on multiple mutations are highly desirable. We describe a critical role of CDK6 in the survival of ⁺ AML cells as palbociclib induced apoptosis not only in ⁺ cells but also in ⁻D835Y⁺ cells. Antineoplastic effects were also seen in primary patient-derived cells and in a xenograft model, where therapy effectively suppressed tumor formation in vivo at clinically relevant concentrations. In cells with ⁻ITD or -TKD mutations, the CDK6 protein not only affects cell cycle progression but also transcriptionally regulates oncogenic kinases mediating intrinsic drug resistance, including AURORA and AKT-a feature not shared by its homolog CDK4. While AKT and AURORA kinase inhibitors have significant therapeutic potential in AML, single agent activity has not been proven overly effective. We describe synergistic combination effects when applying these drugs together with palbociclib which could be readily translated to patients with AML bearing or ⁻TKD mutations. Targeting synergistically acting vulnerabilities, with CDK6 being the common denominator, may represent a promising strategy to improve AML patient responses and to reduce the incidence of selection of resistance-inducing mutations.
尽管在急性髓细胞白血病（AML）的治疗方面已经取得了重大进展，但并非所有患者都能治愈。FLT3 受体酪氨酸激酶在大约 1/3 的新发性 AML 中发生突变，是药物开发的一个有吸引力的靶点，其激活突变位于膜近侧结构域（内部串联重复，ITD）或酪氨酸激酶结构域（TKD），最常见于密码子 D835。虽然小分子酪氨酸激酶抑制剂（TKI）能有效地靶向 ITD 突变形式，但对 TKD 的突变则没有反应。此外，由于突变耐药性，FLT3 抑制并不能在患者中诱导持续的反应。因此，迫切需要具有更广泛抑制多种突变作用的更有效化合物。我们描述了 CDK6 在 ⁺ AML 细胞存活中的关键作用，因为 palbociclib 不仅诱导 ⁺细胞凋亡，而且诱导 ⁻D835Y⁺细胞凋亡。在原代患者来源细胞和异种移植模型中也观察到了抗肿瘤作用，在该模型中，在临床相关浓度下，治疗有效地抑制了体内肿瘤的形成。在具有 ⁻ITD 或 -TKD 突变的细胞中，CDK6 蛋白不仅影响细胞周期进程，而且转录调控介导内在药物耐药性的致癌激酶，包括 AURORA 和 AKT-这一特征与它的同源物 CDK4 不同。虽然 AKT 和 AURORA 激酶抑制剂在 AML 中有显著的治疗潜力，但单一药物的活性尚未被证明过于有效。我们描述了将这些药物与 palbociclib 联合应用时的协同组合效应，这可能很容易转化为携带 ⁻TKD 突变的 AML 患者。针对协同作用的脆弱性，以 CDK6 为共同分子，可能代表改善 AML 患者反应和减少诱导耐药性突变选择的有希望的策略。
