Both conventional and targeted treatments of cancer are effective only in subsets of patients. A major obstacle for any treatment directed against a certain tumor type is the biological heterogeneity of tumors. Therefore, characterization of treatment-relevant tumor heterogeneity is necessary to develop more specific, tumor-tailored treatments in the future. Here, we evaluated heterogeneity among alveolar rhabdomyosarcoma (aRMS) by assessing differences in anti-apoptotic signaling mediated by FGFR4, a receptor commonly activated in this tumor type. We found that FGFR4 signaling rescues subgroups of aRMS cell lines from apoptosis induced by compounds targeting the IGF1R-PI3K-mTor pathway or by different chemotherapeutics. As a result of differences of involved apoptotic signaling mechanisms composition of the subgroups is compound-dependent. IGF1R-PI3K-mTor targeted treatment induced apoptosis via Bim/Bad in the rescue and via Bmf in the non-rescue group of cells. Gene expression analysis detected signatures specific for these two cell types also in biopsy samples. Expression levels of AP2β discriminate the two cell types and reveal that both cell types are present in different ratios in most aRMS tumors. Behaviour of Rh30 cells suggests that the two cell types reflect different activation states of PAX/FKHR, the fusion transcription factors present in most aRMS and that environmental stimuli can induce a phenotype switch. Combination of targeted or untargeted drugs with FGFR inhibitors therefore represents an opportunity to improve therapeutic efficacy against aRMS cells with active anti-apoptotic FGFR4 signaling.

Citation Format: Marco Wachtel, Jelena Rakic, Michal Okoniewski, Peter Bode, Beat Schäfer. FGFR4-mediated anti-apoptotic signaling classifies subtypes of alveolar rhabdomyosarcoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5592. doi:10.1158/1538-7445.AM2013-5592

©2013 American Association for Cancer Research
2013