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

Neuroblastoma (NB) is a pediatric tumor of the peripheral nervous system, with approximately 80% of relapsed cases exhibiting RAS-MAPK pathway mutations that activate ERK, promoting cell proliferation and drug resistance. Ulixertinib, a first-in-class ERK-specific inhibitor, has demonstrated promising antitumor activity in phase 1 clinical trials for advanced solid tumors. In this study, we show that ulixertinib significantly and dose-dependently inhibits cell proliferation and colony formation across various NB cell lines, including PDX cells. Transcriptomic analysis revealed that ulixertinib extensively suppresses multiple oncogenic and neuronal developmental pathways, such as EGFR, VEGF, WNT, MAPK, NGF, and NTRK1. Proteomic analysis further indicated that ulixertinib disrupts the cell cycle and promotes apoptosis in NB cells. Additionally, ulixertinib treatment significantly enhanced the sensitivity of NB cells to the conventional chemotherapeutic agent doxorubicin. Moreover, ulixertinib effectively inhibited NB tumor growth and prolonged overall survival in treated mice across two different NB mouse models. Our preclinical findings suggest that ulixertinib, either as a monotherapy or in combination with existing treatments, offers a novel and promising therapeutic strategy for NB.