C-Kit as an Oncogenic Tyrosine Kinase - Regulation and Dysregulation of Signaling Pathways

It is well known that increased growth and survival of cancer cells often is a result of dysregulated kinase activity and aberrant kinase signaling. The receptor tyrosine kinase c-Kit and its ligand SCF are contributors to this phenomenon in a variety of human cancers, for example hematological malignancies, germ cell tumors and gastrointestinal stromal tumors.
In this thesis I have investigated signaling events downstream of the activated c-Kit receptor. We compared two isoforms of c-Kit in SCF-induced signal transduction and we demonstrated both cell-type specific as well as isoform-specific differences in the activation of the PI3-kinase pathway.
Moreover, we examined differences in the activation and downstream signaling between wild-type c-Kit and the oncogenic version c-Kit/D816V. We found that c-Kit/D816V has an altered substrate specificity that resembles that of Src kinases and therefore circumvents the need for Src family kinases in c-Kit-mediated signal transduction. Increased knowledge of the regulation and control of c-Kit activity is the key to understand the mechanisms causing its oncogenic activation.
One of our major findings is a new oncogenic property of SCF, as a proangiogenic factor. We present evidence of SCF-induced accumulation of the transcription factor HIF-1 in normoxia and subsequently increased levels of the vascular endothelial growth factor (VEGF). VEGF is the major contributor of the neoangiogenesis which tumors cells are dependent on for survival and metastasis.
The involvement of c-Kit and other kinases in the progression of cancer makes kinases suitable targets for drug design. Improved understanding of detailed c-Kit signaling is required to be able to design more specific inhibitors as well as for the selection of patients for targeted therapies. The therapeutic potential of targeting kinases in cancer treatment is an interesting approach that so far is a successful story in the case of Imatinib treatment of patients with gastrointestinal stromal tumors and certain types of leukemia.