Targeted ferroptosis induction enhances chemotherapy efficacy in chemoresistant neuroblastoma.

Neuroblastoma (NB) is an aggressive pediatric solid tumor which often develops chemoresistance. Ferroptosis is a potential vulnerability in NB, but its interplay with chemoresistance and standard-of-care chemotherapy is not known. Here, we report that key antioxidant pathways are enriched in refractory NB, and that ferroptosis can be induced in NB through various mechanisms of action (MOA) in vitro and in vivo. We observed that NB standard-of-care chemotherapy can interfere with certain ferroptosis-inducing mechanisms, particularly those targeting GPX4, and that the combination of ferroptosis-inducing drugs with current clinical therapy should be based on MOA. Our work also shows that a combination of chemotherapy and the thioredoxin reductase inhibitor Auranofin counteracted some of the anti-ferroptotic effects of chemotherapy and the combination outperformed chemotherapy alone, resulting in increased survival in a chemoresistant NB patient-derived xenograft model. The combination of Auranofin and chemotherapy decreased the population of immature mesenchymal-like NB cells in vivo and exerted its effect through ferritinophagy, lysosome accumulation and iron overload. Thus, upon careful selection of the MOA, the inclusion of ferroptosis-inducing agents within a clinically relevant treatment protocol is feasible and can outperform standard-of-care chemotherapy in high-risk NB.