ERK Inhibitor Ulixertinib Inhibits High-Risk Neuroblastoma Growth In Vitro and In Vivo

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Neuroblastoma (NB) is a pediatric peripheral nervous system tumor.
• RAS-MAPK pathway mutations activate ERK in 80% of relapsed NB, promoting proliferation and drug resistance.

Purpose of the Study:

• To evaluate the efficacy of ulixertinib, an ERK-specific inhibitor, in preclinical neuroblastoma models.
• To investigate the molecular mechanisms underlying ulixertinib's antitumor activity.
• To assess the potential of ulixertinib in combination with conventional chemotherapy.

Main Methods:

• Treatment of NB cell lines and patient-derived xenograft (PDX) cells with ulixertinib.
• Transcriptomic and proteomic analyses to identify inhibited pathways.
• Assessment of ulixertinib's effect on cell cycle, apoptosis, and chemosensitization.
• Evaluation of ulixertinib efficacy in NB mouse models.

Main Results:

• Ulixertinib dose-dependently inhibited NB cell proliferation and colony formation.
• Ulixertinib suppressed oncogenic and neuronal developmental pathways (EGFR, VEGF, WNT, MAPK, NGF, NTRK1).
• Ulixertinib induced cell cycle arrest, promoted apoptosis, and sensitized NB cells to doxorubicin.
• Ulixertinib inhibited tumor growth and improved survival in NB mouse models.

Conclusions:

• Ulixertinib demonstrates significant preclinical efficacy against neuroblastoma.
• Ulixertinib targets key oncogenic pathways implicated in NB progression.
• Ulixertinib represents a promising therapeutic strategy for neuroblastoma, alone or in combination therapy.