Abstract
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.
Highlights
Chronic lymphocytic leukemia (CLL) remains incurable with standard therapies [1]
We show that the combination of idelalisib and GS-9973 synergistically decreases CLL cell viability in the majority of CLL samples tested
Significant growth inhibition was seen in the presence of HS-5 conditioned media and in patient derived primary bone marrow CLL cells, which are known to have an activated phenotype [13] and be more resistant to cytotoxic therapy [14], [15]
Summary
Chronic lymphocytic leukemia (CLL) remains incurable with standard therapies [1]. Increasingly it has been recognized that CLL cell survival is dependent on the complex interactions of neoplastic cells with the microenvironment. Treatment of primary CLL cells with idelalisib (GS-1101), ibrutinib, and fostamatinib (R406) which inhibit the PI3 kinase delta-specific isoform (PI3Kd), Bruton’s tyrosine kinase (Btk) and spleen tyrosine kinase (Syk) respectively, results in inhibition of BCR signaling pathways, decreased cell proliferation, and disruption of chemokine mediated CLL cell migration [5],[6],[7],[8]. These agents are orally bioavailable and have been evaluated in early phase trials in relapsed and refractory CLL patients. New therapeutic approaches that evaluate these agents in combination are warranted
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