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

Yang Yu, Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Yanling Zhao, Texas Children's Hospital, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Jongmin Choi, Advanced Technology Cores/Office of Research, Baylor College of Medicine, Houston, TX 77030, USA.
Zhongcheng Shi, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77003, USA.
Linjie Guo, Texas Children's Hospital, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
John Elizarraras, Texas Children's Hospital, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Andy Gu, Texas Children's Hospital, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Feng Cheng, Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Yanxin Pei, Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Dai Lu, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA.
Muller Fabbri, Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Saurabh Agarwal, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Chunchao Zhang, Texas Children's Hospital, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Sung Yun Jung, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77003, USA.
Jennifer H. Foster, Texas Children's Hospital, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Jianhua Yang, Center for Cancer and Immunology Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.

Document Type

Journal Article

Publication Date

11-10-2022

Journal

Cancers

Volume

14

Issue

22

DOI

10.3390/cancers14225534

Keywords

ERK inhibition; c-Myc/N-Myc; combination therapy; neuroblastoma; ulixertinib

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.

Department

Pediatrics

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