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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5549-5557.
Prepublished online as a Blood First Edition Paper on March 24, 2009; DOI 10.1182/blood-2008-06-165068.
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Submitted June 24, 2008
Accepted March 10, 2009
Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach
Matthias Niedermeier, Bryan T. Hennessy, Zachary A. Knight, Marina Henneberg, Jianhua Hu, Antonina V. Kurtova, William G. Wierda, Michael J. Keating, Kevan M. Shokat, and Jan A. Burger*
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
Department of Systems Biology and Gynecologic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, United States
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: jaburger{at}mdanderson.org.
Phosphoinositide 3-kinases (PI3Ks) are among the most frequently activated signaling pathways in cancer. In Chronic Lymphocytic Leukemia (CLL), signals from the microenvironment are critical for the expansion of the malignant B cells, and cause constitutive activation of PI3Ks. CXCR4 is a key receptor for CLL cell migration and adhesion to marrow stromal cells (MSC). Because of the importance of CXCR4 and PI3Ks for CLL-microenvironment cross-talk, we investigated the activity of novel, isoform-selective PI3K inhibitors that target different isoforms of the p110 kDa subunit. Inhibition with p110 inhibitors (PIK-90 and PI-103) resulted in a significant reduction of chemotaxis and actin polymerization to CXCL12 and reduced migration beneath MSC (pseudoemperipolesis). Western blot and reverse phase protein array analyses consistently demonstrated that PIK-90 and PI-103 inhibited phosphorylation of Akt and S6, whereas p110 or p110 /p110 inhibitors were less effective. In suspension and MSC co-cultures, PI-103 and PIK-90 were potent inducers of CLL cell apoptosis. Moreover, these p110 inhibitors enhanced the cytotoxicity of fludarabine and reversed the protective effect of MSC on fludarabine-induced apoptosis. Collectively, our data demonstrate that p110 inhibitors antagonize stromal cell-derived migration-, survival-, and drug resistance-signals, and therefore provide a rational to explore the therapeutic activity of these promising agents in CLL.
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