FGFR-mediated anti-apoptotic signaling identifies novel subgroups in alveolar rhabdomyosarcoma

Biological heterogeneity represents a major obstacle for cancer treatment. Therefore, characterization of treatment-relevant tumor heterogeneity is necessary to develop more effective therapies in the future. Here, we uncovered population heteroge- neity among PAX/FOXO1-positive alveolar rhabdomyosarcoma by characterizing prosurvival networks initiated by FGFR4 signal- ing. We found that FGFR4 signaling rescues only subgroups of alveolar rhabdomyosarcoma cells from apoptosis induced by compounds targeting the IGF1R-PI3K-mTOR pathway. Differences in both proapoptotic machinery and FGFR4-activated signal- ing are involved in the different behavior of the phenotypes. Proapoptotic stress induced by the kinase inhibitors is sensed by Bim/Bad in rescue cells and by Bmf in nonrescue cells. Anti-apoptotic ERK1/2 signaling downstream of FGFR4 is long-lasting in rescue and short-termed in most non-rescue cells. Gene expression analysis detected signatures specific for these two groups also in biopsy samples. The different cell phenotypes are present in different ratios in alveolar rhabdomyosarcoma tumors and can be identified by AP2b expression levels. Hence, inhibiting FGFR signaling might represent an important strat- egy to enhance efficacy of current RMS treatment