A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor
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Russell T Burke1, Sarah Meadows2, Marc M Loriaux1,4, Kevin S. Currie3, Scott A. Mitchell3, Patricia Maciejewski3, Astrid S. Clarke3, Julie A. Dipaolo3, Brian J. Druker1,5, Brian J. Lannutti2 ,and Stephen E. Spurgeon1,6
1 Knight Cancer Institute, Oregon Health & Science University, Portland, OR.
2 Gilead Sciences Inc, Seattle, WA
3 Gilead Sciences Inc, Branford, CT
4 Division of Pathology, Oregon Health & Science University, Portland, OR
5 Howard Hughes Medical Institute, Bethesda, MD
6 Division of Hematology and Medical Oncology, Oregon Health & Science University
Stephen E. Spurgeon, email:
Keywords: Chronic Lymphocytic Leukemia, B-cell receptor, signaling pathways, spleen tyrosine kinase, PI3 kinase
Received: October 9, 2013 Accepted: October 28, 2013 Published: October 30, 2013
Agents that target B-cell receptor (BCR) signaling in lymphoid malignancies including idelalisib (GS-1101) and fostamatinib which inhibit the delta isoform of PI3 kinase (PI3Kd) and spleen tyrosine kinase (Syk) respectively have shown significant clinical activity. By disrupting B-cell signaling pathways, idelalisib treatment has been associated with a dramatic lymph node response, but eradication of disease and relapse in high risk disease remain challenges. Targeting the BCR signaling pathway with simultaneous inhibition of PI3Kd and Syk has not yet been reported. We evaluated the pre-clinical activity of idelalisib combined with the novel and selective Syk inhibitor GS-9973 in primary peripheral blood and bone marrow Chronic Lymphocytic Leukemia (CLL) samples. Both PI3Kd and Syk inhibition reduced CLL survival and in combination induced synergistic growth inhibition and further disrupted chemokine signaling at nanomolar concentrations including in bone marrow derived and poor risk samples. Simultaneous targeting of these kinases may significantly increase clinical activity.
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