Oncotarget

Priority Research Papers:

Targeting BCR-ABL+ stem/progenitor cells and BCR-ABL-T315I mutant cells by effective inhibition of the BCR-ABL-Tyr177-GRB2 complex

Min Chen, Ali G. Turhan, Hongxia Ding, Qingcong Lin, Kun Meng _ and Xiaoyan Jiang

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Oncotarget. 2017; 8:43662-43677. https://doi.org/10.18632/oncotarget.18216

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Abstract

Min Chen1, Ali G. Turhan2, Hongxia Ding3, Qingcong Lin3, Kun Meng3 and Xiaoyan Jiang1

1 Terry Fox Laboratory, British Columbia Cancer Agency and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

2 Department of Hematology, Paris Sud University Hospitals, University Paris Sud 11 and INSERM U935, Villejuif, France

3 Shenogen Pharma Group Ltd, Beijing, China

Correspondence to:

Kun Meng, email:

Xiaoyan Jiang, email:

Keywords: BCR-ABL+ human leukemia, leukemic stem cells, tyrosine kinase inhibitors, Icaritin (SNG162 and SNG1153), ERα36

Received: April 05, 2017 Accepted: May 07, 2017 Published: May 25, 2017

Abstract

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.


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