Combined MEK and YAP inhibition in a mouse model of neuroblastoma: A promising approach for minimal residual disease.

Abstract

BACKGROUND: The cure rate of high-risk neuroblastoma remains unsatisfactory, necessitating the development of novel therapies. We previously reported the in vitro and in vivo efficacy of trametinib (TR), a MEK inhibitor, in neuroblastoma. The administration of TR further prolonged survival in a mouse model of neuroblastoma with minimal residual disease (MRD), which mimics post-tumorectomy residuals. However, the acquisition of resistance to long-term TR administration with YAP activation in the Hippo pathway remains an issue. This study investigated the efficacy of combining TR with CA3, a YAP inhibitor, in MRD. METHODS: Human neuroblastoma cells were injected into the renal capsule of mice. In the MRD groups, tumors were completely resected. The sham group underwent skin incision alone. Each group was further divided into TR monotherapy and TR/CA3 combination therapy groups and monitored for 16 weeks (4 groups in total, 5 mice each). Tumor size was measured using an IVIS imaging system. Progression-free survival (PFS) and overall survival (OS) were evaluated using the log-rank test. RESULTS: Two out of five mice treated with TR/CA3 combination therapy in the MRD group did not show tumor regrowth during the 16-week observation period, and a decreased tumor volume was maintained in one mouse. In the MRD group, PFS was significantly extended by TR/CA3 combination therapy in comparison to the TR monotherapy (p = 0.02). In the sham group, TR/CA3 combination therapy also significantly prolonged PFS relative to TR monotherapy (p < 0.01). All MRD mice survived in both the TR monotherapy and TR/CA3 combination therapy subgroups. In the sham group, TR/CA3 combination therapy significantly improved OS relative to TR monotherapy (p = 0.03). CONCLUSION: TR/CA3 combination therapy showed the greatest efficacy in the MRD group. Relative to TR monotherapy, TR/CA3 combination therapy achieved greater inhibition of tumor growth and extended PFS. These results suggest that in minimal residual neuroblastoma tumors, the combined use of CA3 with TR may not only inhibit tumor growth but also reduce tumor volume.