Targeting BCR-ABL+ stem/progenitor cells and BCR-ABL-T315I mutant cells by effective inhibition of the BCR-ABL-Tyr177-GRB2 complex
| Autor: | Qingcong Lin, Min Chen, Kun Meng, Hongxia Ding, Xiaoyan Jiang, Ali G. Turhan |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Icaritin (SNG162 and SNG1153) Fusion Proteins bcr-abl CD34 Gene Expression leukemic stem cells Models Biological 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases tyrosine kinase inhibitors medicine Humans Chromans Phosphorylation Progenitor cell Protein Kinase Inhibitors Cell Proliferation GRB2 Adaptor Protein biology Cell growth business.industry Cell Membrane Estrogen Receptor alpha Myeloid leukemia 3. Good health Dasatinib BCR-ABL+ human leukemia Protein Transport 030104 developmental biology ERα36 Amino Acid Substitution Oncology 030220 oncology & carcinogenesis Mutation Immunology Neoplastic Stem Cells biology.protein Cancer research GRB2 business Estrogen receptor alpha Priority Research Paper Protein Binding medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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