title: A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor.
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.
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, OR.
authors.forename: Russell T
authors.initials: RT
authors.lastname: Burke
authors.forename: Sarah
authors.initials: S
authors.lastname: Meadows
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Currie
authors.forename: Scott A
authors.initials: SA
authors.lastname: Mitchell
authors.forename: Patricia
authors.initials: P
authors.lastname: Maciejewski
authors.forename: Astrid S
authors.initials: AS
authors.lastname: Clarke
authors.forename: Julie A
authors.initials: JA
authors.lastname: Dipaolo
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lannutti
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Spurgeon
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D052999:Quinazolinones / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D009025:Morpholines
chemical_list: D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011687:Purines; D011719:Pyrazines; D052999:Quinazolinones; D000072377:Syk Kinase; C000589391:6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; D009025:Morpholines; C000606896:SYK protein, human; C552946:idelalisib