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GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways

Wei Ye, Zhiwu Jiang, Xiaoyun Lu, Xiaomei Ren, Manman Deng, Shouheng Lin, Yiren Xiao, Simiao Lin, Suna Wang, Baiheng Li, Yi Zheng, Peilong Lai, Jianyu Weng, Donghai Wu, Yuguo Ma, Xudong Chen, Zhesheng Wen, Yaoyu Chen, Xiaoyan Feng, Yangqiu Li, Pentao Liu, Xin Du, Duanqing Pei, Yao Yao, Bing Xu, Ke Ding and Peng Li _

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Oncotarget. 2017; 8:87002-87015. https://doi.org/10.18632/oncotarget.10881

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Abstract

Wei Ye1,2,3,4,*, Zhiwu Jiang2,3,4,*, Xiaoyun Lu2, Xiaomei Ren2, Manman Deng5, Shouheng Lin2,3,4, Yiren Xiao2,3,4, Simiao Lin2,3,4, Suna Wang2,3,4, Baiheng Li2,3,4, Yi Zheng2,3,4, Peilong Lai6, Jianyu Weng6, Donghai Wu3,4, Yuguo Ma7, Xudong Chen8, Zhesheng Wen9, Yaoyu Chen10, Xiaoyan Feng11, Yangqiu Li12,13, Pentao Liu14, Xin Du6, Duanqing Pei3,4, Yao Yao15, Bing Xu5, Ke Ding2 and Peng Li2,3,4

1School of Life Science, University of Science and Technology of China, Anhui, China

2State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

3Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

4Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

5Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, China

6Department of Hematology, Guangdong Provincial People’s Hospital, Guangzhou, China

7Yikang Tailai Technology Co. Ltd, Guangzhou, China

8Department of Interventional Radiology, Shenzhen People’s Hospital, Shenzhen, China

9Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China

10First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China

11Chongqing HiChuang Biomedical Corp., Chongqing, China

12Department of Hematology, Medical College, Jinan University, Guangzhou, China

13Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China

14Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, England, UK

15Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

*Indicates co-first authorship

Correspondence to:

Peng Li, email: [email protected]

Ke Ding, email: [email protected]

Keywords: pre-B ALL, GZD824, SRC, PI3K/AKT, PDX

Received: January 27, 2016    Accepted: June 09, 2016    Published: July 28, 2016

ABSTRACT

Available therapeutic options for advanced B cell precursor acute lymphoblastic leukemia (pre-B ALL) are limited. Many lead to neutropenia, leaving patients at risk of life-threatening infections and result in bad outcomes. New treatment options are needed to improve overall survival. We previously showed that GZD824, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells and tumor models. Here, we show that GZD824 decreases cell viability, induces cell-cycle arrest, and causes apoptosis in pre-B ALL cells. Furthermore, Ph– pre-B ALL cells were more sensitive to GZD824 than Ph+ pre-B ALL cells. GZD824 consistently reduced tumor loads in Ph– pre-B ALL xenografts but failed to suppress Ph+ pre-B ALL xenografts. GZD824 decreased phosphorylation of SRC kinase, STAT3, RB and C-myc. It also downregulated the expression of BCL-XL, CCND1 and CDK4 and upregulated expression of CCKN1A. Expression of IRS1 was decreased in GZD824-treated pre-B ALL cells, blocking the PI3K/AKT pathway. These data demonstrate that GZD824 suppresses pre-B ALL cells through inhibition of the SRC kinase and PI3K/AKT pathways and may be a potential therapeutic agent for the management of pre-B ALL.


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