Abstract 3418: Characterization of a survival pathway controlled by FGFR4 in alveolar Rhabdomyosarcoma

Abstract

Abstract The inefficiency of the currently used conventional treatment modalities for alveolar Rhabdomyosarcoma (aRMS) stimulate the search for alternative treatment approaches such as targeted therapies exploiting addiction of tumors cells to specific signalling pathways. Indeed, inhibition of specific nodal points in such pathways such as growth factor receptors (e.g. IGF1R) was effective in preclinical model systems of aRMS and might advance to early clinical studies. However, experience from clinical studies of adult tumors suggests that tumor cells can escape such therapies targeting solely one signalling molecule via (re)activation of alternative pathways. Therefore, the evolution of tumor resistance needs to be addressed already in preclinical studies and might then be targeted upfront by employing an evidence-based combination approach. Here, we describe a FGFR regulated survival pathway which is able to rescue aRMS cells from apoptosis induced by blocking other growth factor pathways. The relevant receptor is FGFR4, a direct target of the oncogenic PAX3/FKHR fusion protein, whose activation efficiently blocks apoptosis induced by an IGF1R inhibitor in different aRMS cell lines. On the other hand, combined inhibition of both FGFR4 and IGF1R pathways synergistically reduces aRMS cell viability, involving upregulation of Bcl-xl. Interestingly, the survival pathway downstream of FGFR4 does neither involve MEK/ERK nor Akt. Experiments defining the components of this pathway using genetic siRNA screens are currently underway. Taken together, our data hint to a potential escape mechanism of tumor cells from therapies targeting the IGF1R/AKT axis via FGFR4 and suggests that combined inhibition of the FGFR4 and IGF1R pathways might be superior to single treatments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3418.