Targeting c-Kit mutations: basic science to novel therapies.
The Kit receptor tyrosine kinase is a transmembrane receptor that is expressed in a variety of different tissues and mediates pleiotropic biological effects through its ligand stem cell factor (SCF). Sporadic mutations of Kit as well as autocrine/paracrine activation mechanisms of the SCF/Kit pathway have been implicated in a variety of malignancies, where its primary contribution to metastases is in enhancing tumor growth and reducing apoptosis. For example, Kit is frequently mutated and activated in gastrointestinal stromal tumors (GISTs) and there is ligand-mediated activation of Kit in some lung cancers. Kit is a convenient target in Kit-induced tumors and inhibition of this receptor with the small molecule drug Gleevec (imatinib mesylate, STI571) in GIST has shown dramatic efficacy. Unfortunately, past experience has demonstrated that chemotherapy of cancers with a single drug often leads to resistance of the cancer. Further understanding of the molecular mechanisms underlying Kit-mediated transformation is therefore important and may lead to the identification of further novel drug targets. These Kit-specific signaling pathways may then be targeted to overcome potential drug resistance. This review will focus on our understanding of the molecular mechanisms involved in transformation by Kit. The potential mechanisms by which Kit induces cellular transformation are described. We will also discuss the role and expression of Kit in various malignancies. Ultimately, the understanding of c-Kit biology, biochemistry, and mutational analysis will lead to better therapeutics.
Sattler
Martin
M
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Salgia
Ravi
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000209:etiology*; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019009:Proto-Oncogene Proteins c-kit