Inhibition of Interleukin-1 Receptor-Associated Kinase-1 by Pacritinib Is a Therapeutic Strategy to Overcome Melanoma Resistance.

Despite advancements in systemic therapy, the mortality rate for patients with metastatic melanoma remains around 70%, underscoring the imperative for alternative treatment strategies. Through the establishment of a chemoresistant melanoma model and a subsequent drug investigation, we have identified pacritinib, a medication designed for treating myelofibrosis and severe thrombocytopenia, as a potential candidate to overcome resistance to melanoma therapy. Our research reveals that pacritinib, administered at clinically achievable concentrations, effectively targets dacarbazine-resistant melanoma cells by suppressing IRAK1 rather than JAK2. Notably, melanoma-resistant cells exhibit elevated p-IRAK1 levels, while there is no discernible difference in p-JAK2 levels between sensitive and resistant cells. Additionally, analysis of melanoma patients indicates a higher expression of IRAK1, correlating with a significantly improved survival rate. Furthermore, the depletion of IRAK1 not only reduces cell viability in melanoma cells but also enhances the effectiveness of dacarbazine treatment. In a dacarbazine-resistant melanoma model, pacritinib demonstrates significant inhibition of tumor growth in mice, leading to enhanced overall survival. In the dacarbazine-sensitive melanoma model, the combination of pacritinib and dacarbazine is more effective than dacarbazine alone in reducing tumor growth and improving overall survival in mice. In summary, our findings highlight IRAK1 as a promising therapeutic target to overcome melanoma resistance, and pacritinib emerges as a valuable addition to the treatment armamentarium for melanoma.