title: Dasatinib worsens the effect of cetuximab in combination with fractionated radiotherapy in FaDu- and A431-derived xenografted tumours.
abstract: BACKGROUND
  Cetuximab is often combined with radiotherapy in advanced SCCHN. Alternative routes bypassing inhibition of EGFR with cetuximab may overshadow the efficacy of this combination. We undertook this study to investigate a possible role of dasatinib in this scenario.
  
  
  METHODS
  The SCC5, SCC25, SCC29, FaDu and A431 cell lines were assessed in vitro for cell proliferation under cetuximab and dasatinib treatments. In FaDu and A431 cells, dasatinib plus cetuximab resulted in higher proliferation than cetuximab alone. Then, FaDu and A431 cells were implanted into subcutaneous tissue of athymic mice that were irradiated with 30 Gy in 10 fractions over 2 weeks, and treated with cetuximab and dasatinib. Tumour growth, DNA synthesis and angiogenesis were determined. The EGFR, RAS-GTP activity, phosphorylated AKT, ERK1/2, SRC protein levels and VEGF secretion were determined in vitro.
  
  
  RESULTS
  The addition of dasatinib to cetuximab and radiotherapy increased tumour growth, DNA synthesis and angiogenesis that were associated with RAS, AKT and ERK1/2 activation, and SRC inhibition in FaDu and A431 cells.
  
  
  CONCLUSIONS
  In xenografts derived from these two cell lines, dasatinib did not improve the efficacy of cetuximab combined with radiotherapy. On the contrary, it worsened tumour control achieved by the combination of these two treatments.
authors: Laboratory of Translational Research, Catalan Institute of Oncology, Avda. Gran de L'Hospitalet 199-203, 08907 L'Hospitalet de Llobregat, Spain.
authors: M
authors: M
authors: Baro
authors: Laboratory of Translational Research, Catalan Institute of Oncology, Avda. Gran de L'Hospitalet 199-203, 08907 L'Hospitalet de Llobregat, Spain.
authors: L I
authors: LI
authors: de Llobet
authors: Laboratory of Translational Research, Catalan Institute of Oncology, Avda. Gran de L'Hospitalet 199-203, 08907 L'Hospitalet de Llobregat, Spain.
authors: A
authors: A
authors: Figueras
authors: Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors: I
authors: I
authors: Skvortsova
authors: Department of Medical Oncology, Catalan Institute of Oncology, Avda. Gran de L'Hospitalet 199-203, 08907 L'Hospitalet de Llobregat, Spain.
authors: R
authors: R
authors: Mesia
authors: 1] Laboratory of Translational Research, Catalan Institute of Oncology, Avda. Gran de L'Hospitalet 199-203, 08907 L'Hospitalet de Llobregat, Spain [2] Department of Radiation Oncology, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors: J
authors: J
authors: Balart
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000068818:Cetuximab; D004261:DNA Replication; D000069439:Dasatinib; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000532:radiotherapy; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C412373:AG 1879; D061067:Antibodies, Monoclonal, Humanized; D011743:Pyrimidines; D013844:Thiazoles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; D018631:ras Proteins; D000068818:Cetuximab; D000069439:Dasatinib