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

Abstract

// Tiago Elias Heinen 1, 2 , Rafael Pereira dos Santos 1, 2 , Amanda da Rocha 1, 2 , Michel Pinheiro dos Santos 3 , Patrícia Luciana da Costa Lopez 1, 2 , Marco Aurélio Silva Filho 1, 2 , Bárbara Kunzler Souza 1, 2 , Luís Fernando da Rosa Rivero 4 , Ricardo Gehrke Becker 5 , Lauro José Gregianin 1, 6, 8 , Algemir Lunardi Brunetto 7 , André Tesainer Brunetto 7 , Caroline Brunetto de Farias 1, 7 , Rafael Roesler 1, 2 1 Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil 2 Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil 3 Faculty of Health Sciences, UniRitter Laureate International Universities, Porto Alegre, RS, Brazil 4 Departament of Pathology, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil 5 Department of Orhopaedics and Traumatology, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil 6 Department of Pediatrics, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil 7 Children’s Cancer Institute (ICI), Porto Alegre, RS, Brazil 8 Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil Correspondence to: Rafael Roesler, e-mail: rafael.roesler@pq.cnpq.br Keywords: TrkA, TrkB, neurotrophin, neurotrophin receptor, Ewing sarcoma Received: October 05, 2015      Accepted: April 10, 2016      Published: April 26, 2016 ABSTRACT 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.