靶向酪氨酸激酶的抗肿瘤药物联合新型PKC激活剂FTC诱导分化治疗急性髓系白血病的分子机制研究

Aberrant activation of protein tyrosine kinases (PTK) plays an important role in pathogenesis of acute myeloid leukemia (AML). Much attention has been put into the discovery of drugs and protocols targeting PTK. The differentiation therapy of all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) making this disease highly curable, suggests that the release of differentiation block may be an opportunity to cure AML. Our previous work indicated that a natural small molecule compound FTC is a potent differentiation-inducing agent and protein kinase C (PKC) is proved to be its pharmacological target. It was also showed that PTK-targeted anticancer drugs could enhance the AML cell differentiation induced by FTC. Based on these results, this study will be designed to screen the optimizing combination, which includes PTK-targeted anticancer drugs and FTC, for synergistic induction of AML cell differentiation. The therapeutic effect of these combinations will be then evaluated on the animal models and clinical samples. It will be thoroughly investigated that PKC and PTK with their mediating signaling pathways. The molecular targets for the synergistic induction of AML cell differentiation will further be explored by using the advanced proteomic methods. Total these findings will reveal the molecular mechanisms underlying the synergistic induction of AML cell differentiation by PTK-targeted anticancer drugs combined with FTC. Novel therapeutic schedule(s) and drug target(s) will eventually be provided for the differentiation therapy of AML.

酪氨酸激酶（PTK）的异常激活在急性髓系白血病（AML）发病进程中发挥重要作用，以PTK为靶点的药物研发和治疗方案已成为研究热点。ATRA诱导分化治疗使APL成为可被治愈的白血病，提示解除细胞分化阻滞是治愈AML的可能途径。前期工作发现天然小分子化合物FTC是一个潜在的白血病靶向诱导分化治疗药物，证实蛋白激酶C（PKC）是FTC的药理作用靶点，研究还发现靶向PTK的抗肿瘤药物能够增强FTC诱导AML细胞分化。基此，本课题拟通过细胞分化模型筛选，发现靶向PTK的抗肿瘤药物协同FTC诱导AML细胞分化的最佳组合，并在动物模型和临床病例样本上对其进行疗效评价；深入研究PTK和PKC及其介导的信号转导通路，并应用前沿的蛋白质组学研究手段，发现协同诱导AML细胞分化的候选作用靶点，揭示靶向PTK的抗肿瘤药物联合FTC诱导AML细胞分化的分子机制，最终为诱导分化治疗AML提供新的治疗方案和药物靶点。

酪氨酸激酶（PTK）的异常激活在急性髓系白血病（AML）发病进程中发挥重要作用，以PTK为靶点的药物研发和治疗方案已成为研究热点。新型蛋白激酶C（PKC）激动剂FTC是一个潜在的白血病靶向诱导分化治疗药物。本研究首先通过活性筛选发现系列靶向PTK的抗肿瘤药物能够联合FTC增强AML细胞分化，其中Imatinib、Saracatinib分别与FTC联合诱导分化活性最强，而Nilotinib无活性；结果显示FTC与Imatinib或Saracatinib联用显著增强AML细胞分化，抑制细胞增殖，并诱导细胞周期G1期阻滞；与此相反，Nilotinib显著拮抗上述联合诱导细胞分化作用。作用机制研究表明，单独高浓度FTC通过激活ERK并下调c-Myc表达，发挥其诱导AML细胞分化活性；与此相一致，酪氨酸激酶抑制剂联合FTC通过进一步增强ERK/MAPK激活，放大对下游信号分子c-Myc下调与P21上调的表达调控，最终增强诱导HL-60细胞分化；进一步研究揭示FTC联合Imatinib诱导的HL-60细胞分化完全依赖RAF-MEK-ERK信号通路，但部分依赖PKC。上述结果提示酪氨酸激酶抑制剂联合FTC可能通过PKC与非PKC依赖途径激活RAF-MEK-ERK-c-Myc信号轴诱导AML细胞分化。因此，本课题的研究结果表明靶向PTK的抗肿瘤药物联合新型PKC激动剂FTC具有显著的诱导AML细胞分化作用，具有潜在的诱导分化治疗AML的潜力。