Ferroptosis-Inducing Drug Auranofin Shows Promise in Combination with Chemotherapy for Resistant Neuroblastoma
Key Insights
Researchers identified ferroptosis, an iron-dependent cell death pathway, as a crucial vulnerability in chemoresistant neuroblastoma (search) cells, with high antioxidant pathway activity correlating with poor patient prognosis.
The study revealed that standard chemotherapy can interfere with certain ferroptosis-inducing agents, particularly GPX4 (search) inhibitors like RSL3, due to chemotherapy-mediated upregulation of ferroptosis resistance mechanisms.
Auranofin, an FDA-approved gold-based drug, demonstrated additive effects when combined with COJEC (search) chemotherapy, working through ferritinophagy-mediated iron overload and phenotypic differentiation in preclinical models.
Researchers have identified a promising new approach to treating chemoresistant neuroblastoma (search) (NB), a challenging childhood cancer, by targeting ferroptosis—an iron-dependent form of cell death. The study, published in NPJ Precision Oncology, demonstrates that combining the FDA-approved drug Auranofin with standard chemotherapy can overcome treatment resistance in high-risk neuroblastoma (search).
Ferroptosis Emerges as Key Vulnerability in Resistant Tumors
The research team analyzed multiple patient cohorts and found that high activity of three antioxidant pathways—glutathione, mevalonate, and thioredoxin—strongly correlates with poor prognosis in neuroblastoma (search) patients. These pathways help cancer cells resist ferroptosis, a form of cell death triggered by iron accumulation and lipid peroxidation.
"High expression of these pathways correlated with high-risk factors and an overall worse survival," the researchers reported. Analysis of patient tumor samples before and after chemotherapy revealed that treatment significantly upregulated these antioxidant pathways, suggesting that chemotherapy itself may promote ferroptosis resistance.
Complex Interactions Between Chemotherapy and Ferroptosis Induction
The study evaluated 16 different ferroptosis-inducing compounds across multiple patient-derived organoid models. While most drugs showed effectiveness in at least one model, only four demonstrated consistent activity: Auranofin, ML162, RSL3, and salinomycin.
However, when researchers tested combinations with COJEC (search) chemotherapy (the standard clinical protocol combining cisplatin, vincristine, etoposide, cyclophosphamide, and carboplatin), they discovered unexpected antagonistic effects with certain drugs. RSL3, a GPX4 (search) inhibitor, showed reduced effectiveness when combined with chemotherapy, with an average Bliss synergy score of -10.089 in one model.
"The antagonism observed between RSL3 and COJEC (search) appears to be mediated by GPX4 (search) upregulation," the researchers explained. They found that etoposide, a component of COJEC, particularly interfered with GPX4 inhibition by upregulating ferroptosis resistance genes including GPX4, FSP1 (search), and HSPB1 (search).
Auranofin Demonstrates Superior Combination Potential
In contrast to GPX4 (search) inhibitors, Auranofin—which targets thioredoxin reductase (search)—showed additive effects when combined with COJEC (search) chemotherapy. The drug works through a distinct mechanism involving ferritinophagy, a specialized form of autophagy that degrades iron-storage proteins and leads to toxic iron accumulation.
RNA sequencing analysis revealed that Auranofin treatment upregulated autophagy pathways and genes involved in iron metabolism, including NCOA4 (search) (which mediates ferritinophagy) and MCOLN1 (which transports iron from lysosomes). The combination also countered several chemotherapy-induced changes that could limit treatment effectiveness, including upregulation of the multidrug resistance protein MRP1 (search) and the stem cell marker CD44.
Promising Preclinical Results in Resistant Models
In patient-derived xenograft studies using chemoresistant neuroblastoma (search) models, the Auranofin-COJEC (search) combination demonstrated significant therapeutic benefit. Mice treated with the combination showed slower tumor growth and extended survival compared to chemotherapy alone.
Histological analysis revealed increased markers of ferroptosis (4HNE and CD71), iron accumulation, and oxidative damage in treated tumors. Importantly, the combination appeared to shift tumor cells from an aggressive, undifferentiated phenotype toward a more differentiated state, as evidenced by reduced SOX9 expression and increased tyrosine hydroxylase staining.
"The combination of COJEC (search) and Auranofin resulted in significantly slower tumor growth and increased survival in this chemoresistant HR-NB PDX model," the researchers reported.
Clinical Translation Considerations
The study highlights the importance of mechanism-based drug selection when developing ferroptosis-targeting therapies. While multiple compounds can induce ferroptosis, their compatibility with existing chemotherapy regimens varies significantly based on their molecular targets and mechanisms of action.
Auranofin offers particular advantages for clinical translation, as it is already FDA-approved for other indications and is currently being explored in cancer clinical trials. The drug's ability to target multiple pathways—including ferroptosis induction, multidrug resistance reversal, and phenotypic differentiation—may contribute to its effectiveness in combination therapy.
Implications for Treatment Strategy
The findings suggest that ferroptosis-inducing agents could be incorporated into first-line treatment protocols to prevent the development of chemoresistance. However, the research emphasizes that drug selection must be based on careful consideration of molecular mechanisms and potential interactions with chemotherapy components.
"Our work shows the potential of therapeutically targeting ferroptosis in HR-NB and demonstrates both the feasibility and the challenges of including ferroptosis-inducing agents as part of a clinically relevant treatment protocol," the authors concluded.
The study provides a framework for developing personalized combination therapies that could improve outcomes for children with high-risk neuroblastoma (search), particularly those with chemoresistant disease. Future clinical trials will be needed to validate these findings and determine optimal dosing strategies for pediatric patients.