title: SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma.
abstract: BACKGROUND
  Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma.
  
  
  METHODS
  The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130(CAS)), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft.
  
  
  RESULTS
  Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days).
  
  
  CONCLUSIONS
  Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tokuhisa
authors.forename: Michael E
authors.initials: ME
authors.lastname: Lidsky
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Toshimitsu
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Turley
authors.forename: Georgia M
authors.initials: GM
authors.lastname: Beasley
authors.forename: Tomio
authors.initials: T
authors.lastname: Ueno
authors.forename: Ketan
authors.initials: K
authors.lastname: Sharma
authors.forename: Christina K
authors.initials: CK
authors.lastname: Augustine
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008558:Melphalan / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D060888:Real-Time Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D019009:Proto-Oncogene Proteins c-kit; D019061:src-Family Kinases; D008558:Melphalan; D000069439:Dasatinib