Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs
Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs
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DOI：
10.1073/pnas.0400063101
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发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Neel, BG
中科院分区：
文献类型：
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作者：
Mohi, MG;Boulton, C;Neel, BG
异常蛋白酪氨酸激酶（PTKs）引起许多人类白血病。例如，BCR/ABL导致慢性髓性白血病（CML），而FLT 3突变有助于急性髓性白血病的发病机制。ABL抑制剂伊马替尼（Gleevec，STI 571）对于治疗慢性期CML具有显著的功效，并且FLT 3抑制剂（例如，PKC 412）在临床前研究中显示出类似的前景。然而，对PTK抑制剂的耐药性是一个主要的新兴问题，可能会限制长期治疗效果。可能需要开发合理的联合疗法来有效治愈这些和其他肿瘤性疾病。在这里，我们报告说，mTOR抑制剂雷帕霉素协同伊马替尼对BCR/ABL转化的骨髓和淋巴细胞，并增加生存在小鼠CIVIL模型。雷帕霉素/伊马替尼组合也抑制伊马替尼耐药的BCR/ABL突变体，雷帕霉素加PKC 412协同抑制表达PKC 412敏感或耐药的致白血病FLT 3突变体的细胞。生化分析提出了抑制4 E-BP 1磷酸化可能对PTK抑制剂/雷帕霉素组合的协同作用特别重要的可能性。向雷帕霉素或雷帕霉素加PTK抑制剂中加入丝裂原活化蛋白激酶激酶抑制剂进一步增加了功效。我们的研究结果表明，同时靶向致白血病PTKs所需的一种以上的信号通路可能会改善FLT 3突变引起的原发性和复发性CML和/或急性髓细胞性白血病的治疗。类似的策略可用于治疗与突变和/或过表达的PTK相关的实体瘤。
Abnormal protein tyrosine kinases (PTKs) cause many human leukemias. For example, BCR/ABL causes chronic myelogenous leukemia (CML), whereas FLT3 mutations contribute to the pathogenesis of acute myelogenous leukemia. The ABL inhibitor Imatinib (Gleevec, STI571) has remarkable efficacy for treating chronic phase CML, and FLT3 inhibitors (e.g., PKC412) show similar promise in preclinical studies. However, resistance to PTK inhibitors is a major emerging problem that may limit long-term therapeutic efficacy. Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders. Here, we report that the mTOR inhibitor rapamycin synergizes with Imatinib against BCR/ABL-transformed myeloid and lymphoid cells and increases survival in a murine CIVIL model. Rapamycin/Imatinib combinations also inhibit Imatinib-resistant mutants of BCR/ABL, and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412-sensitive or resistant leukemogenic FLT3 mutants. Biochemical analyses raise the possibility that inhibition of 4E-BP1 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor/rapamycin combinations. Addition of a mitogen-activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy. Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and/or acute myelogenous leukemia caused by FLT3 mutations. Similar strategies may be useful for treating solid tumors associated with mutant and/or overexpressed PTKs.