The PI3-Kinase Delta Inhibitor Idelalisib (GS-1101) Targets Integrin-Mediated Adhesion of Chronic Lymphocytic Leukemia (CLL) Cell to Endothelial and Marrow Stromal Cells

• DOI: 10.1371/journal.pone.0083830
• Publication Date: 2013-12-23T22:24:58Z
• Authors: Stefania Fiorcari; Wells S. Brown; Bradley W. McIntyre; Zeev Estrov; Rossana Maffei; Susan O’Brien; Mariela Sivina; Julia Hoellenriegel; William G. Wierda; Michael J. Keating; Wei Ding; Neil E. Kay; Brian J. Lannutti; Roberto Marasca; Jan A. Burger
• Keywords: Idelalisib

CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor causes rapid lymph node shrinkage, along with increase in lymphocytosis, prior to inducing objective responses patients. This characteristic activity presumably due redistribution from tissues into blood, but underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on adhesion endothelial bone marrow stromal cells (EC, BMSC). found that inhibited EC BMSC under static shear flow conditions. TNFα-induced VCAM-1 (CD106) expression supporting layers increased accentuated inhibitory effect idelalisib. Co-culture also protected undergoing apoptosis, this EC- BMSC-mediated protection was antagonized by Furthermore, we demonstrate VLA-4 (CD49d) resulted phosphorylation Akt, which sensitive inhibition These findings interferes integrin-mediated BMSC, providing novel mechanism explain idelalisib-induced blood.