GZD824 Suppresses the Growth of Human B Cell Precursor Acute Lymphoblastic Leukemia Cells by Inhibiting the SRC Kinase and PI3K/AKT Pathways

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Nov 21

PMID 29152059

Citations 14

Authors

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

Peng Li

Affiliations

Soon will be listed here.

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 , and and upregulated expression of . 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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