Chen Min, Turhan Ali G, Ding Hongxia, Lin Qingcong, Meng Kun, Jiang Xiaoyan
Terry Fox Laboratory, British Columbia Cancer Agency and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Department of Hematology, Paris Sud University Hospitals, University Paris Sud 11 and INSERM U935, Villejuif, France.
Oncotarget. 2017 Jul 4;8(27):43662-43677. doi: 10.18632/oncotarget.18216.
Treatment of BCR-ABL+ human leukemia has been significantly improved by ABL tyrosine kinase inhibitors (TKIs), but they are not curative for most patients and relapses are frequently associated with BCR-ABL mutations, warranting new targets for improved treatments. We have now demonstrated that protein expression of human estrogen receptor alpha 36 (ERα36), an alternative splicing variant of human estrogen receptor alpha 66 (ERα66), is highly increased in TKI-insensitive CD34+ chronic myeloid leukemia (CML) cells and BCR-ABL-T315I mutant cells, and is abnormally localized in plasma membrane and cytoplasm. Interestingly, new pre-clinically-validated analogs of Icaritin (SNG162 and SNG1153), which target abnormal ERα36 activity, inhibit cell growth and induce apoptosis of BCR-ABL+ leukemic cells, particularly BCR-ABL-T315I mutant cells. A combination of SNG inhibitors and TKI selectively eliminates treatment-naïve TKI-insensitive stem/progenitor cells while sparing healthy counterparts. Oral TKI dasatinib combined with potent SNG1153 inhibitor effectively eliminates infiltrated BCR-ABL+ blast cells and enhances survival of mice. Importantly, a unique mechanism of SNG inhibition was uncovered by demonstrating a marked interruption of the BCR-ABLTyr177-GRB2 interaction, leading to inhibition of the downstream RAS/MAPK pathway. This new combination therapy may lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.
ABL酪氨酸激酶抑制剂（TKIs）显著改善了BCR-ABL+人类白血病的治疗效果，但它们对大多数患者并非治愈性药物，复发常与BCR-ABL突变相关，因此需要新的治疗靶点来改善治疗。我们现已证明，人类雌激素受体α 66（ERα66）的可变剪接变体人类雌激素受体α 36（ERα36）的蛋白表达在对TKI不敏感的CD34+慢性髓性白血病（CML）细胞和BCR-ABL-T315I突变细胞中高度增加，且在质膜和细胞质中异常定位。有趣的是，靶向异常ERα36活性的新的临床前验证的淫羊藿素类似物（SNG162和SNG1153）可抑制细胞生长并诱导BCR-ABL+白血病细胞凋亡，尤其是BCR-ABL-T315I突变细胞。SNG抑制剂与TKI联合使用可选择性消除未经治疗的对TKI不敏感的干/祖细胞，同时保留健康细胞。口服TKI达沙替尼与强效SNG1153抑制剂联合使用可有效消除浸润的BCR-ABL+原始细胞并提高小鼠存活率。重要的是，通过证明BCR-ABLTyr177-GRB2相互作用的明显中断，揭示了SNG抑制的独特机制，从而导致下游RAS/MAPK途径的抑制。这种新的联合疗法可能会更有效地根除疾病，尤其是在TKI耐药和疾病进展风险高的患者中。
