The ability of the N-MYC
transcription factor to drive
cancer progression is well demonstrated in
neuroblastoma, the most common extracranial pediatric solid
tumor, where MYCN amplification heralds a poor prognosis, with only 11% of high-risk patients surviving past 5 years. However, decades of attempts of direct inhibition of N-MYC or its paralogues has led to the conclusion that this
protein is "undruggable." Therefore, targeting pathways upregulated by N-MYC signaling presents an alternative therapeutic approach. Here, we show that MYCN-amplified
neuroblastomas are characterized by elevated rates of
protein synthesis and that high expression of ABCE1, a translation factor directly upregulated by N-MYC, is itself a strong predictor of poor clinical outcome. Despite the potent ability of N-MYC in heightening
protein synthesis and malignant characteristics in
cancer cells, suppression of ABCE1 alone selectively negated this effect, returning the rate of translation to baseline levels and significantly reducing the growth, motility, and invasiveness of MYCN-amplified
neuroblastoma cells and patient-derived xenograft
tumors in vivo. The growth of nonmalignant cells or MYCN-nonamplified
neuroblastoma cells remained unaffected by reduced ABCE1, supporting a therapeutic window associated with targeting ABCE1.
Neuroblastoma cells with c-MYC overexpression also required ABCE1 to maintain cell proliferation and translation. Taken together, ABCE1-mediated translation constitutes a critical process in the progression of N-MYC-driven and c-MYC-driven
cancers that warrants investigations into methods of its therapeutic inhibition. SIGNIFICANCE: These findings demonstrate that N-MYC-driven
cancers are reliant on elevated rates of
protein synthesis driven by heightened expression of ABCE1, a vulnerability that can be exploited through suppression of ABCE1.