A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor
Citations Over TimeTop 10% of 2014 papers
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.
Related Papers
- → BLNK mediates Syk-dependent Btk activation(2001)139 cited
- → Targets for Ibrutinib Beyond B Cell Malignancies(2015)127 cited
- → Highly Potent BTK Degradation Induced By NRX0492 As a Therapeutic Strategy for CLL(2019)3 cited
- → Abstract 3761: HSK26784: An oral PROTAC-BTK degrader for multiple B lymphocyte derived malignancies(2020)
- → Idelalisib, Ibrutinib Show Benefits in CLL(2014)