title: Identification of p38β as a therapeutic target for the treatment of Sézary syndrome.
abstract: Cutaneous T-cell lymphomas (CTCLs) represent a group of hematopoietic malignancies that home to the skin and have no known molecular basis for disease pathogenesis. Sézary syndrome (SS) is the leukemic variant of CTCL. Currently, CTCL is incurable, highlighting the need for new therapeutic modalities. We have previously observed that combined small-molecule inhibition of protein kinase C-β (PKCβ) and glycogen synthase kinase 3 (GSK3) causes synergistic apoptosis in CTCL cell lines and patient cells. Through microarray analysis of a SS cell line, we surveyed global gene expression following combined PKCβ-GSK3 treatment to elucidate therapeutic targets responsible for cell death. Clinically relevant targets were defined as genes differentially expressed in SS patients that were modulated by combination-drug treatment of SS cells. Gene set enrichment analysis uncovered candidate genes enriched for an immune-cell signature, specifically the T-cell receptor and mitogen-activated protein kinase signaling pathways. Further analysis identified p38 as a potential therapeutic target that is overexpressed in SS patients and decreased by synergistic-inhibitor treatment. This target was verified through small-molecule inhibition of p38, leading to cell death in both SS cell lines and patient cells. These data establish p38 as a SS biomarker and a potential therapeutic target for the treatment of CTCL.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Bliss-Moreau
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA.
authors.forename: Preethi H
authors.initials: PH
authors.lastname: Gunaratne
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Guitart
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Krett
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; City of Hope Comprehensive Cancer Center, Duarte, California, USA. Electronic address: srosen@coh.org.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D020935:MAP Kinase Signaling System; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors; D012751:Sezary Syndrome / Q000188:drug therapy* / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D064546:Protein Kinase C beta; D048290:Mitogen-Activated Protein Kinase 11; D038362:Glycogen Synthase Kinase 3