Oncotarget

Research Papers:

Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia

Xiang Wang, Xi Zhang, Ben-shang Li, Xiaowen Zhai, Zhuo Yang, Li-xia Ding, Hongsheng Wang, Chris Liang, Weiliang Zhu, Jian Ding and Ling-hua Meng _

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Oncotarget. 2014; 5:10732-10744. https://doi.org/10.18632/oncotarget.2533

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Abstract

Xiang Wang1, Xi Zhang1, Ben-shang Li3, Xiaowen Zhai4, Zhuo Yang2, Li-xia Ding3, Hongsheng Wang4, Chris Liang5, Weiliang Zhu2, Jian Ding1 and Ling-hua Meng1

Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

Department of Hematology and Oncology, Shanghai Jiaotong University School of Medicine, Shanghai, China

Department of Hematology and Oncology, Children’s Hospital of Fudan University, Shanghai, China

Xcovery, LLC, West Palm Beach, Florida, USA

Correspondence:

Ling-hua Meng , email:

Jian Ding, email:

Keywords: PI-3Kdelta inhibitor, MAPK, B cell acute lymphocytic leukemia, target therapy

Received: August 01, 2014 Accepted: September 25, 2014 Published: September 26, 2014

Abstract

B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3Kδ displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3Kδ selective inhibitor X-370, which displays distinct binding mode with p110δ and blocks constitutively active or stimulus-induced PI3Kδ signaling. X-370 significantly inhibited survival of human B cell leukemia cells in vitro, with associated induction of G1 phase arrest and apoptosis. X-370 abrogated both Akt and Erk1/2 signaling via blockade of PDK1 binding to and/or phosphorylation of MEK1/2. Forced expression of a constitutively active MEK1 attenuated the antiproliferative activity of X-370. X-370 preferentially inhibited the survival of primary pediatric B-ALL cells displaying PI3Kδ-dependent Erk1/2 phosphorylation, while combined inhibition of PI3Kδ and MEK1/2 displayed enhanced activity. We conclude that PI3Kδ inhibition led to abrogation of both Akt and Erk1/2 signaling via a novel PI3K-PDK1/MEK1/2-Erk1/2 signaling cascade, which contributed to its efficacy against B-ALL. These findings support the rationale for clinical testing of PI3Kδ inhibitors in pediatric B-ALL and provide insights needed to optimize the therapeutic strategy.


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