Molecular framework for response to imatinib mesylate in systemic sclerosis.
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.
Chung
Lorinda
L
Stanford University, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
Fiorentino
David F
DF
Benbarak
Maya J
MJ
Adler
Adam S
AS
Mariano
Melissa M
MM
Paniagua
Ricardo T
RT
Milano
Ausra
A
Connolly
M Kari
MK
Ratiner
Boris D
BD
Wiskocil
Robert L
RL
Whitfield
Michael L
ML
Chang
Howard Y
HY
Robinson
William H
WH
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
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