title: Imatinib targeting of KIT-mutant oncoprotein in melanoma.
abstract: OBJECTIVE
  Melanoma subtypes based on anatomic location and UV light exposure can be further classified based on genetic alterations recently identified. Mutations and gene amplification in KIT have been described in a significant percentage of mucosal and acral melanomas. We recently reported a patient with metastatic mucosal melanoma harboring a known KIT mutation treated with imatinib mesylate who experienced a major response. Biological effects of KIT inhibition in these melanomas remain poorly understood. We sought to investigate further the effects of imatinib in these melanoma subsets.
  
  
  METHODS
  Mucosal melanoma cells were analyzed for KIT aberrations by genomic sequencing, quantitative PCR, and single nucleotide polymorphism analyses. Imatinib effects were assayed by viability measurements and apoptotic cytotoxicity. Tumor cell lysates were assayed by Western blots to determine effects on multiple signaling pathways after imatinib exposure.
  
  
  RESULTS
  Mucosal melanoma cells exhibited imatinib sensitivity correlating with KIT mutational status. Imatinib dramatically decreased proliferation and was cytotoxic to a KIT mutated and amplified cell culture. Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways.
  
  
  CONCLUSIONS
  Rational targeting of KIT in melanoma offers a unique and potent clinical opportunity. In vitro analyses revealed major sensitivity to KIT kinase inhibition by imatinib, with potent induction of melanoma cell apoptosis. Biochemical studies identified changes in signaling molecules regulating proliferation and survival responses, which may serve as mediators and/or biomarkers of in vivo treatment efficacy. Pathways affected by KIT inhibition provide a model for understanding components in effective melanoma cell death and insights into targeting for resistance mechanisms.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jiang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Noah K
authors.initials: NK
authors.lastname: Yuen
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Hans R
authors.initials: HR
authors.lastname: Widlund
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001549:Benzamides; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D009092:Mucous Membrane / Q000473:pathology; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit