title: Janus and PI3-kinases mediate glucocorticoid resistance in activated chronic leukemia cells.
abstract: Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis. The JAK1/2 inhibitor ruxolitinib blocked STAT3-phosphorylation and partially improved DEX-mediated killing of stimulated CLL cells in vitro but not in CLL patients in vivo. An automated microscopy-based screen of a kinase inhibitor library implicated an additional protective role for the PI3K/AKT/FOXO pathway. Blocking this pathway with the glycolysis inhibitor 2-deoxyglucose (2-DG) or the PI3K-inhibitors idelalisib and buparlisib increased DEX-mediated killing but did not block STAT3-phosphorylation. Combining idelalisib or buparlisib with ruxolitinib greatly increased killing by DEX. These observations suggest that glucocorticoid resistance in CLL cells may be overcome by combining JAK and PI3K inhibitors.
authors: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors: Sina
authors: S
authors: Oppermann
authors: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors: Avery J
authors: AJ
authors: Lam
authors: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: Stephanie
authors: S
authors: Tung
authors: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors: Yonghong
authors: Y
authors: Shi
authors: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors: Lindsay
authors: L
authors: McCaw
authors: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors: Guizhei
authors: G
authors: Wang
authors: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors: Jarkko
authors: J
authors: Ylanko
authors: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors: Brian
authors: B
authors: Leber
authors: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors: David
authors: D
authors: Andrews
authors: Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors: David E
authors: DE
authors: Spaner
mesh_terms: D019008:Drug Resistance, Neoplasm; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D005938:Glucocorticoids; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases
keywords: FOXO; STAT3; chronic lymphocytic leukemia; cytokines; glucocorticoids