FGFR4 is highly overexpressed in Rhabdomyosarcoma tumors and contains activating mutations in eight percent of the cases. These data strongly suggest that FGFR4 plays an important role in the tumorigenesis of this cancer type. However, the molecular mechanisms behind the benefit of active FGFR4 for Rhabdomyosarcoma cells are largely unknown.

Here, we describe a survival pathway activated by FGFR4 in Rhabdomyosarcoma cells. Active FGFR4 is able to block apoptosis induced by inhibition of other central signaling pathways with small molecule inhibitors, such as the IGF1R pathway with AEW541 and PI3K-controlled pathways with BEZ235. Using different biochemical and genetic approaches, we could locate the apoptotic block upstream of the pro-apoptotic BH3-only proteins bmf and bim. To further elucidate the mechanism of this prosurvival signaling, we then performed proteomic studies to define the complete interactome of FGFR4 in Rhabdomyosarcoma cells. These analyses revealed a strong interaction of FGFR4 with PLCγ, linking FGFR signaling to PKCs. Indeed, activation of PKCs strongly inhibits AEW541/BEZ253-induced apoptosis, suggesting that PKCs are central for FGFR4-activated survival signaling. In contrast, the classical survival pathways via Akt and Erk are not or only marginally involved in the rescue mechanism.

Treatment approaches targeting the IGF1R/PI3K axis in Rhabdomyosarcoma are under intensive investigation. Our data suggest that rescue mechanisms via FGFR4 and PKCs should be taken into account when applying such treatment strategies. A combination of IGF1R- and FGFR4/PKC-inhibitors therefore might be superior compared to single treatments.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2151. doi:10.1158/1538-7445.AM2011-2151

©2011 American Association for Cancer Research
2011