Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs).
Most gastrointestinal stromal tumors (GISTs) express constitutively activated forms of the KIT receptor tyrosine kinase protein, resulting from oncogenic mutations in the extracellular, juxtamembrane, or kinase domains. KIT oncoproteins are detected early in GIST tumorigenesis, and most GIST patients respond well to treatment with the KIT kinase inhibitor imatinib mesylate (STI571, Gleevec). However, GISTs can develop resistance to imatinib, and additional therapeutic strategies are needed. Little is known about oncogenic KIT signal transduction in GISTs, and whether the type of KIT mutation accounts for selective activation of downstream signaling intermediates. We therefore evaluated KIT downstream signaling profiles in 15 primary GISTs with mutations in KIT exons 9, 11, 13, and 17, and in two human GIST cell lines. All GISTs showed constitutive phosphorylation at KIT tyrosine residues Y703 and Y721. Additionally, most GISTs showed activation of MAPK p42/44, AKT, S6K, STAT1, and STAT3. STAT5 and JNK were not demonstrably activated in any GIST. Using GIST in vitro models, we showed that activation of MAPK p42/44, AKT, and S6K was KIT dependent, whereas STAT1 and STAT3 phosphorylation was only partially dependent on KIT activation. Correlation of activated signaling pathways with the type of KIT mutation revealed low levels of AKT phosphorylation in exon 9 mutant GISTs in contrast to a subset of GISTs with exon 11 mutations. However, additional factors are likely to modify the engagement of signaling pathways in GISTs as suggested by the fact that four GISTs with identical KIT exon 9 mutations had differential activation of MAPK p42/44 and STAT proteins. In summary, in this first report on KIT signal transduction in primary GISTs and GIST cell lines, we identified pathways that are constitutively activated in a KIT-dependent manner and therefore warrant further study as molecular targets in GISTs.
Duensing
Anette
A
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. aduensing@rics.bwh.harvard.edu
Medeiros
Fabiola
F
McConarty
Bryna
B
Joseph
Nora E
NE
Panigrahy
Dipak
D
Singer
Samuel
S
Fletcher
Christopher D M
CD
Demetri
George D
GD
Fletcher
Jonathan A
JA
D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000378:metabolism*; D006801:Humans; D008297:Male; D015513:Oncogene Proteins / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
D015513:Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit