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

• Published in: Oncotarget 2016-06, Vol.7 (23), p.34860-34880
• Main Authors: Heinen, Tiago Elias, Dos Santos, Rafael Pereira, da Rocha, Amanda, Dos Santos, Michel Pinheiro, Lopez, Patrícia Luciana da Costa, Silva Filho, Marco Aurélio, Souza, Bárbara Kunzler, Rivero, Luís Fernando da Rosa, Becker, Ricardo Gehrke, Gregianin, Lauro José, Brunetto, Algemir Lunardi, Brunetto, André Tesainer, de Farias, Caroline Brunetto, Roesler, Rafael
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Azepines - pharmacology; Benzamides - pharmacology; Brain-Derived Neurotrophic Factor - biosynthesis; Brain-Derived Neurotrophic Factor - genetics; Carbazoles - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Doxorubicin - pharmacology; Enzyme Inhibitors - pharmacology; Etoposide - pharmacology; Humans; Indole Alkaloids - pharmacology; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Nerve Growth Factor - biosynthesis; Nerve Growth Factor - genetics; Receptor, trkA - antagonists & inhibitors; Receptor, trkA - biosynthesis; Receptor, trkA - genetics; Receptor, trkB - antagonists & inhibitors; Receptor, trkB - biosynthesis; Receptor, trkB - genetics; Research Paper; RNA, Messenger - biosynthesis; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - pathology; Tubulin - metabolism; Vincristine - pharmacology
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8992

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.