title: Molecular framework for response to imatinib mesylate in systemic sclerosis.
abstract: Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFRbeta and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10(-8)). The response of these patients and the findings of the analyses suggest that PDGFRbeta and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc.
authors.affiliation: Stanford University, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
authors.forename: Lorinda
authors.initials: L
authors.lastname: Chung
authors.forename: David F
authors.initials: DF
authors.lastname: Fiorentino
authors.forename: Maya J
authors.initials: MJ
authors.lastname: Benbarak
authors.forename: Adam S
authors.initials: AS
authors.lastname: Adler
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Mariano
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Paniagua
authors.forename: Ausra
authors.initials: A
authors.lastname: Milano
authors.forename: M Kari
authors.initials: MK
authors.lastname: Connolly
authors.forename: Boris D
authors.initials: BD
authors.lastname: Ratiner
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wiskocil
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
mesh_terms: D001549:Benzamides; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D008875:Middle Aged; D016374:Oncogene Proteins v-abl / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D045743:Scleroderma, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D001549:Benzamides; D016374:Oncogene Proteins v-abl; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta