1. ERK Inhibitor Ulixertinib Inhibits High-Risk Neuroblastoma Growth In Vitro and In Vivo.
- Author
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Yu, Yang, Zhao, Yanling, Choi, Jongmin, Shi, Zhongcheng, Guo, Linjie, Elizarraras, John, Gu, Andy, Cheng, Feng, Pei, Yanxin, Lu, Dai, Fabbri, Muller, Agarwal, Saurabh, Zhang, Chunchao, Jung, Sung Yun, Foster, Jennifer H., and Yang, Jianhua
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THERAPEUTIC use of antineoplastic agents , *IN vitro studies , *NERVE growth factor , *BIOLOGICAL models , *NEUROBLASTOMA , *IN vivo studies , *GENETIC mutation , *COMBINATION drug therapy , *PROTEIN kinase inhibitors , *EPIDERMAL growth factor receptors , *ANIMAL experimentation , *CELL receptors , *DRUG resistance , *CELLULAR signal transduction , *CELL cycle , *PROTEOMICS , *TRANSFERASES , *GENE expression profiling , *CELL proliferation , *MOLECULAR structure , *MICE - Abstract
Simple Summary: Neuroblastoma (NB) is the most common extracranial solid tumor in children, and the majority of patients with high-risk disease are unable to be cured. There is an urgent need to design novel therapeutics for NB patients. In NB, the RAS-MAPK pathway plays a crucial role in essential processes such as cell proliferation, survival, and chemoresistance. In the present study, we determined the therapeutic potential of the ERK inhibitor ulixertinib in NB using a panel of NB cell lines, patient-derived xenograft (PDX) cell lines, and NB xenograft mouse models. Ulixertinib significantly and potently inhibited NB cell proliferation and tumor growth, as well as prolonged survival in the treated mice. Additionally, ulixertinib synergistically sensitized NB cells to the conventional chemotherapeutic drug doxorubicin. This study provides proof-of-concept pre-clinical evidence for exploring ulixertinib as a novel therapeutic approach for NB. 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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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