Simultaneous targeting of PI3Kδ and a PI3Kδ-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia
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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
1 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
3 Department of Hematology and Oncology, Shanghai Jiaotong University School of Medicine, Shanghai, China
4 Department of Hematology and Oncology, Children’s Hospital of Fudan University, Shanghai, China
5 Xcovery, LLC, West Palm Beach, Florida, USA
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
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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