title: Therapeutic targeting of c-KIT in cancer.
abstract: BACKGROUND
  Mutated forms of the receptor tyrosine kinase c-KIT are "drivers" in several cancers and are attractive targets for therapy. While benefits have been obtained from use of inhibitors of KIT kinase activity such as imatinib, especially in gastrointestinal stromal tumours (GIST), primary resistance occurs with certain oncogenic mutations. Furthermore, resistance frequently develops due to secondary mutations. Approaches to addressing both of these issues as well as combination therapies to optimise use of KIT kinase inhibitors are discussed.
  
  
  METHODS
  This review covers the occurrence of oncogenic KIT mutations in different cancers and the molecular basis of their action. The action of KIT kinase inhibitors, especially imatinib, sunitinib, dasatinib and PKC412, on different primary and secondary mutants is discussed. Outcomes of clinical trials in GIST, acute myeloid leukaemia (AML), systemic mastocytosis and melanoma and their implications for future directions are considered.
  
  
  CONCLUSIONS
  Analysis of KIT mutations in individual patients is an essential prerequisite to the use of kinase inhibitors for therapy, and monitoring for development of secondary mutations that confer drug resistance is necessary. However, it is unlikely that KIT inhibitors alone can lead to cure. KIT mutations alone do not seem to be sufficient for transformation; thus identification and co-targeting of synergistic oncogenic pathways should lead to improved outcomes.
authors.affiliation: University of Newcastle, New South Wales, Australia.
authors.forename: Leonie K
authors.initials: LK
authors.lastname: Ashman
authors.forename: Renate
authors.initials: R
authors.lastname: Griffith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit