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Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma

2016; Impact Journals LLC; Volume: 7; Issue: 23 Linguagem: Inglês

10.18632/oncotarget.8992

1949-2553

Tiago Elias Heinen, Rafael Pereira dos Santos, Amanda da Rocha, Michel Pinheiro dos Santos, Patrícia Luciana da Costa Lopez, Marco Aurélio Silva Filho, Bárbara Kunzler Souza, Luís Fernando da Rosa Rivero, Ricardo Gehrke Becker, Lauro José Gregianin, Algemir Lunardi Brunetto, André T. Brunetto, Caroline Brunetto de Farias, Rafael Roesler,

Nerve injury and regeneration

Ewing sarcoma (ES) is a highly aggressive pediatric cancer that may arise from neuronal precursors. Neurotrophins stimulate neuronal devlopment and plasticity. Here, we found that neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as their receptors (TrkA and TrkB, respectively) are expressed in ES tumors. Treatment with TrkA (GW-441756) or TrkB (Ana-12) selective inhibitors decreased ES cell proliferation, and the effect was increased when the two inhibitors were combined. ES cells treated with a pan-Trk inhibitor, K252a, showed changes in morphology, reduced levels of β-III tubulin, and decreased mRNA expression of NGF, BDNF, TrkA and TrkB. Furthermore, combining K252a with subeffective doses of cytotoxic chemotherapeutic drugs resulted in a decrease in ES cell proliferation and colony formation, even in chemoresistant cells. These results indicate that Trk inhibition may be an emerging approach for the treatment of ES.