The novel anticancer agent JNJ-26854165 is active in chronic myeloid leukemic cells with unmutated BCR/ABL and T315I mutant BCR/ABL through promoting proteosomal degradation of BCR/ABL proteins.
The novel anticancer agent JNJ-26854165 is active in chronic myeloid leukemic cells with unmutated BCR/ABL and T315I mutant BCR/ABL through promoting proteosomal degradation of BCR/ABL proteins.
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新型抗癌剂 JNJ-26854165 通过促进 BCR/ABL 蛋白的蛋白酶体降解，对具有未突变 BCR/ABL 和 T315I 突变 BCR/ABL 的慢性粒细胞白血病细胞具有活性
DOI：
10.18632/oncotarget.13951
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发表时间：
2017-01-31
期刊：
影响因子：
--
通讯作者：
Qian W
中科院分区：
文献类型：
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作者：
You L;Liu H;Huang J;Xie W;Wei J;Ye X;Qian W
慢性粒细胞白血病（CML）是一种由BCR/ABL表达引起的克隆性恶性疾病。MDM 2（鼠双微体2的人类同源物）抑制剂如Nutlin-3已被证明以p53依赖的方式诱导CML细胞凋亡并使细胞对伊马替尼敏感。在本文中，我们证明了JNJ-26854165（一种MDM 2抑制剂）在各种BCR/ABL表达细胞中以p53非依赖性方式抑制增殖并触发细胞死亡，这些细胞包括CML急变患者的原代白血病细胞和表达伊马替尼耐药T315 I BCR/ABL突变体的细胞。对JNJ-26854165的应答与BCR/ABL的下调相关，依赖于蛋白体活化。此外，除T315 I突变细胞外，在所有检测的CML细胞中，JNJ-26854165与酪氨酸激酶抑制剂（TKI）伊马替尼或PD 180970联合给药均产生协同效应。总之，我们的结果表明，JNJ-26854165单独使用或与TKI联合使用，代表了一种有前景的新型靶向方法，可克服TKI耐药性并改善CML患者的结局。
Chronic myeloid leukemia (CML) is a clonal malignant disease caused by the expression of BCR/ABL. MDM2 (human homolog of the murine double minute-2) inhibitors such as Nutlin-3 have been shown to induce apoptosis in a p53-dependent manner in CML cells and sensitize cells to Imatinib. Here, we demonstrate that JNJ-26854165, an inhibitor of MDM2, inhibits proliferation and triggers cell death in a p53-independent manner in various BCR/ABL-expressing cells, which include primary leukemic cells from patients with CML blast crisis and cells expressing the Imatinib-resistant T315I BCR/ABL mutant. The response to JNJ-26854165 is associated with the downregulation of BCR/ABL dependently of proteosome activation. Moreover, in all tested CML cells, with the exception of T315I mutation cells, combining JNJ-26854165 and tyrosine kinase inhibitor (TKI) Imatinib or PD180970 leads to a synergistic effect. In conclusion, our results suggest that JNJ-26854165, used either alone or in combination with TKIs, represents a promising novel targeted approach to overcome TKI resistance and improve patient outcome in CML.