THE ETV5 ONCOGENE IS A TARGET OF ACTIVATED ALK SIGNALING IN NEUROBLASTOMA

Neuroblastoma (NB) is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. Current survival rates are still disappointingly low and novel therapeutic venues are needed to improve them. Mutant ALK is currently the most prominent druggable target being present in 10% of NB patients. Unfortunately, in most instances targeted therapies with single compounds lead to resistance and relapse. Therefore, deeper insights into the ALK downstream pathway is critical to understand resistance mechanisms and to identify additional targets for combination therapy. As part of a broader study aimed at dissecting downstream ALK signaling, we observed robust regulation of the oncogene ETV5 in multiple NB cell lines through the ALK-activated RAS/MAPK-axis. Further functional analysis revealed that ALK-mutated NB cell lines depend on ETV5 for proliferation, invasion and colony formation. The effect of ETV5 on proliferation was further supported by mouse xenografts for a NB cell line with stable ETV5 knock-down. Next, transcriptome profiling of both ETV5 knock-down cell lines and xenografts revealed an ETV5 signature which (1) identified patients with poor overall survival, (2) was enriched for an Ewing sarcoma gene signature, suggesting a possible common perturbed gene regulatory pathway and (3) contained CXCR4, an important mediator of invasion and metastasis, and TRIM67, a negative regulator of the RAS-pathway, as possible ETV5 targets. Taken together, we identified ETV5 as an important ALK-MAPK target gene impacting on the ALK driven oncogenic phenotype with CXCR4 and TRIM67 as putative ETV5 effectors which may explain aggressive behaviour and therapy resistance of NB cells.

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