A potential therapeutic strategy for chronic lymphocytic leukemia by combining idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor

Russell T. Burke, Sarah Meadows, Marc M. Loriaux, Kevin S. Currie, Scott A. Mitchell, Patricia Maciejewski, Astrid S. Clarke, Julie A. Dipaolo, Brian J. Druker, Brian J. Lannutti, Stephen E. Spurgeon

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)908-915
Number of pages8
JournalOncotarget
Volume5
Issue number4
DOIs
StatePublished - 2014

Keywords

  • B-cell receptor
  • Chronic lymphocytic leukemia
  • PI3 kinase
  • Signaling pathways
  • Spleen tyrosine kinase

ASJC Scopus subject areas

  • Oncology

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