Dasatinib worsens the effect of cetuximab in combination with fractionated radiotherapy in FaDu- and A431-derived xenografted tumours
Por:
Baro, M, de Llobet, LI, Figueras, A, Skvortsova, I, Mesia, R, Balart, J
Publicada:
23 sep 2014
Resumen:
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.
Filiaciones:
Baro, M:
Catalan Inst Oncol, Lab Translat Res, Lhospitalet De Llobregat 08907, Spain
de Llobet, LI:
Catalan Inst Oncol, Lab Translat Res, Lhospitalet De Llobregat 08907, Spain
Figueras, A:
Catalan Inst Oncol, Lab Translat Res, Lhospitalet De Llobregat 08907, Spain
Skvortsova, I:
Med Univ Innsbruck, Dept Therapeut Radiol & Oncol, A-6020 Innsbruck, Austria
Mesia, R:
Catalan Inst Oncol, Dept Med Oncol, Lhospitalet De Llobregat 08907, Spain
Balart, J:
Catalan Inst Oncol, Lab Translat Res, Lhospitalet De Llobregat 08907, Spain
Hosp Santa Creu & Sant Pau, Dept Radiat Oncol, Barcelona 08025, Spain
Green Published, Hybrid Gold
|