Chromosome 8 gain drives cancer progression by hijacking the translation factor 4E-BP1 sensitizing for targeted CDK4/6 inhibition

To refine patient care in the context of precision oncology, it is increasingly important to understand mechanisms underlying inter-individual tumor heterogeneity, especially in oligomutated cancers. Ewing sarcoma (EwS) is genetically characterized by pathognomonic FET::ETS gene fusions (in most cases EWSR1::FLI1) while featuring a general paucity of other recurrent somatic alterations that might account for observed diversity in clinical patient outcome. Following FET::ETS fusions, chromosome (chr) 8 gain is the second most common recurrent somatic alteration in EwS. However, its pathophysiological role and potential clinical implications remain unclear. Here, we report that gene expression signatures indicative for chr8 gain are significantly associated with poor overall survival of EwS patients, and that this effect is predominantly mediated by expression of the translation initiation factor binding protein EIF4EBP1 (4E-BP1). High EIF4EBP1 expression shows the strongest association with poor overall survival of EwS patients among all genes located on chr8, which as well holds true in a subgroup analysis of patients with localized disease, emphasizing the prognostic role of 4E-BP1 in EwS. Consistently, chr8 gain was associated with higher intra-tumoral EIF4EBP1 expression in EwS patient samples. RNA interference-mediated knockdown of 4E-BP1 significantly decreased proliferation, clonogenicity, and spheroidal growth of EwS cells in vitro as well as tumor growth of EwS xenografts in vivo. To identify potential mechanisms via which 4E-BP1 mediates its phenotypic effect, we performed integrated proteomic and transcriptomic profiling of EwS cell lines with and without silencing of 4E-BP1 revealing that 4E-BP1 guides a multifunctional proteomic network including hubs associated with RNA processing, translational regulation, and chromatin modification. Collectively, we establish a significant association between chr8 gain and unfavorable prognosis in EwS. We show that this association primarily depends on the expression of the translation initiation factor binding protein 4E-BP1 regulating a multifunctional proteomic network. Our data suggest that cytogenetic testing for chr8 gain in EwS tumors may help to improve risk-stratification of patients and adaptation of the therapeutic management.