title: Dasatinib is synergistic with cetuximab and cisplatin in triple-negative breast cancer cells.
abstract: BACKGROUND
  Patients presenting with triple-negative breast cancers (TNBCs) have a poorer prognosis compared with those with other subtypes of breast cancer. The majority of TNBCs overexpress epidermal growth factor receptor (EGFR). However, EGFR inhibition as a monotherapy, as with the monoclonal antibody cetuximab, is ineffective. Src family tyrosine kinases play a critical role in signal transduction downstream of growth factor receptors and are involved in the development of EGFR inhibitor resistance. We hypothesize that dasatinib, an Src family tyrosine kinase inhibitor, may help overcome EGFR resistance to cetuximab, and in combination with cisplatin may enhance growth inhibition and apoptosis and reduce metastatic potential.
  
  
  METHODS
  Growth inhibition, apoptosis, cell migration and invasion, and effects on EGFR, Akt, and mitogen-activated protein kinase phosphorylation were examined in a panel of breast cancer cell lines, including seven TNBC cell lines.
  
  
  RESULTS
  Six out of seven TNBC cell lines demonstrated a synergistic interaction using the triple-drug combination, compared with only two TNBC cell lines with the cisplatin and cetuximab combination. An induction of apoptosis and decrease in EGFR and mitogen-activated protein kinase phosphorylation, and thus resensitization to EGFR inhibition, was observed using the three-drug treatment regimen. A significant reduction (P < 0.001) in tumor cell migration and invasion was also found following dasatinib treatment alone or in combination.
  
  
  CONCLUSIONS
  These findings may have important clinical implications in treating TNBC patients whose tumors co-overexpress both EGFR and c-Src. Identification of this subset of patients may be beneficial in the design of a clinical trial using this treatment regimen.
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan; Department of Surgery, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan. Electronic address: kime@med.wayne.edu.
authors.forename: Elizabeth M H
authors.initials: EM
authors.lastname: Kim
authors.forename: Kelly
authors.initials: K
authors.lastname: Mueller
authors.forename: Elaina
authors.initials: E
authors.lastname: Gartner
authors.forename: Julie
authors.initials: J
authors.lastname: Boerner
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000068818:Cetuximab; D002945:Cisplatin / Q000494:pharmacology*; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D002945:Cisplatin; D000069439:Dasatinib
keywords: Cetuximab; Cisplatin; Dasatinib; EGFR; Src; Triple-negative breast cancer