C-Kit and Gastrointestinal Stromal
Tumors
• By Jessica
Danielle Stewart
http://www.jbc.org/content/vol279/issue30/images/large/zbc0270428710002.jpeg
The Story of KIT is a Familiar
One
(Hint: Think Src and Ras)
A Familiar Story….
• Transmembrane tyrosine kinase receptor
• Stem cell factor (SCF)
• Related to PDGFR α and β, CSF1R, and
FLT3
• First discovered in felines
Heinrich, Michael C, et al. Fig. 2
KIT and the Cell
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Cell proliferation
Cell adhesion
Cell Differentiation
Apoptosis
KIT and the Cell
• “… expressed at high levels in
hematopoietic stem cells, mast cells,
melanocytic cells, germ cells, and
interstitial cells of Cajal (ICC)”. – Heinrich,
Michael C, et al.
Gastrointestinal Stromal Tumors
http://en.wikipedia.org/wiki/Image:GIST_2.jpg
Gastrointestinal Stromal Tumors
(GISTs)
• Rare
• Most frequent mesenchymal tumors of the
digestive tract
What Happens with KIT and Mice?
http://www.spectator.co.nz/images/mice.jpg
KIT and Mice Models
(disruption of KIT)
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absence of functional ICC
aperistalsis of the gut
anemia
white coat color
sterility
KIT and Mouse Models
(gain of function)
• “Sommer et al produced a mouse model
for familial GISTs… patch hyperplasia of
ICCs is evident within the myenteric
plexus for the entire GI tract, and
neoplastic lesions indistinguishable from
human GISTS were observed…”–
Kitamura, et al.
KIT and Mouse Models
(gain of function)
• “Sommer et al produced a mouse model
for familial GISTs… patch hyperplasia of
ICCs is evident within the myenteric
plexus for the entire GI tract, and
neoplastic lesions indistinguishable from
human GISTS were observed…”–
Kitamura, et al.
KIT and Cancer (GISTs)
• KIT is an oncogene
• Usually receptor dimerization occur in the
absence of a ligand
• Might be one of earliest transforming
events in GISTs
• Involved in small cell lung carcinomas,
melanomas, seminomas, and
gastrointestinal stromal tumors
KIT and Cancer (GISTs)
• Mutations affect the kinase and the regulatory
regions
• Different mutations lead to different phenotypes
Heinrich, et al. Fig 4.
KIT and Cancer (GISTs)
• “… the exact signaling pathways activated
by the mutant KIT differ from those
activated by normal KIT. We believe that is
also the case in GISTs where the signaling
cascades governed by KIT oncogenic
activation do not necessarily coincide with
those resulting from ligand mediated
activation of the normal KIT receptor” –
Heinrich, et al 488
Possible Treatments for GISTs
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Surgery (small)
STI – 571
Imatinib mesylate
Sutent
http://www.alibaba.com/photo/10119487
/Rigid_PVC_For_Medicine.jpg
Bibliography
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Chen, Lei L, et al. “A Missense Mutation in KIT Kinase Domain 1 Correlates with
Imatinib Resistance in Gastrointestinal Stromal Tumors”. Cancer Research. 64
(2004): 5913.
“Gastrointestinal Stromal Tumors”
<http://en.wikipedia.org/wiki/Gastrointestinal_stromal_tumor> 3/26/06.
Heinrich, Michael C, et al. “Biology and Genetic Aspects of Gastrointestinal Stromal
Tumors: KIT Activation and Cytogenetic Alterations”. Human Pathology. 33.5 (2002):
484.
“Lab Mice” http://www.spectator.co.nz/images/mice.jpg
Kitamura, Y and S. Hirota. “Kit as a Human Oncogenic Tyrosine Kinase”. Cellular
Molecular Life Science. 61 (2004): 2924.
Marx, Jean. “Encouraging Results for Second-Generation Antiangiogenesis Drugs”.
Science Now. (2005): 29.
Mol, Clifford D, et al. “Structural basis for the Autoinhibition and STI-571 Inhibition of
c-Kit Tyrosine Kinase”. Journal of Biology and Chemistry. 279.30 (2004): 31655.
3/26/06.
http://www.jbc.org/content/vol279/issue30/images/large/zbc0270428710002.jpeg
Tabone, Séverine, et al. “KIT Overexpression and Amplification in Gastrointestinal
Stromal Tumors (GISTs)”. Biochimica et Biophysica Acta (BBA) – Molecular Basis of
Disease. 1741.1-2 (2005): 165.