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Published on: December 7, 2014
ERK Inhibitor Ulixertinib Inhibits High-Risk Neuroblastoma Growth In Vitro and In Vivo
Yang Yu1, Yanling Zhao2, Jongmin Choi3
1Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Abstract:
Neuroblastoma (NB) is a pediatric tumor of the peripheral nervous system. Approximately 80% of relapsed NB show RAS-MAPK pathway mutations that activate ERK, resulting in the promotion of cell proliferation and drug resistance. Ulixertinib, a first-in-class ERK-specific inhibitor, has shown promising antitumor activity in phase 1 clinical trials for advanced solid tumors. Here, we show that ulixertinib significantly and dose-dependently inhibits cell proliferation and colony formation in different NB cell lines, including PDX cells. Transcriptomic analysis revealed that ulixertinib extensively inhibits different oncogenic and neuronal developmental pathways, including EGFR, VEGF, WNT, MAPK, NGF, and NTRK1. The proteomic analysis further revealed that ulixertinib inhibits the cell cycle and promotes apoptosis in NB cells. Additionally, ulixertinib treatment significantly sensitized NB cells to the conventional chemotherapeutic agent doxorubicin. Furthermore, ulixertinib potently inhibited NB tumor growth and prolonged the overall survival of the treated mice in two different NB mice models. Our preclinical study demonstrates that ulixertinib, either as a single agent or in combination with current therapies, is a novel and practical therapeutic approach for NB.
Insights
Ulixertinib effectively inhibits neuroblastoma (NB) cell growth and sensitizes tumors to chemotherapy. This ERK inhibitor shows promise as a novel therapeutic for pediatric neuroblastoma.
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.
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