C-Kit and Gastrointestinal Stromal Tumors

• By Jessica Danielle Stewart

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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

• 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

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Gastrointestinal Stromal Tumors (GISTs)

• Rare

• Most frequent mesenchymal tumors of the digestive tract

What Happens with KIT and Mice?

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KIT and Mice Models(disruption of KIT)

• 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

• Surgery (small)• STI – 571• Imatinib mesylate• Sutent

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Bibliography• 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.