Small molecule inhibitor agerafenib effectively suppresses neuroblastoma tumor growth in mouse models via inhibiting ERK MAPK signaling.

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in early childhood. Despite intensive multimodal therapy, nearly half of children with high-risk disease will relapse with therapy-resistant tumors. Dysregulation of MAPK pathway has been implicated in the pathogenesis of relapsed and refractory NB patients, which underscores the possibility of targeting MAPK signaling cascade as a novel therapeutic strategy. In this study, we found that high expressions of RAF family kinases correlated with advanced tumor stage, high-risk disease, tumor progression, and poor overall survival. Targeted inhibition of RAF family kinases with the novel small molecule inhibitor agerafenib abrogated the activation of ERK MAPK pathway in NB cells. Agerafenib significantly inhibited the cell proliferation and colony formation ability of NB cells in vitro, and its combination with traditional chemotherapy showed a synergistic pro-apoptotic effect. More importantly, agerafenib exhibited a favorable toxicity profile, potently suppressed tumor growth, and prolonged survival in NB mouse models. In conclusion, our preclinical data suggest that agerafenib might be an effective therapeutic agent for NB treatment, both as a single-agent and in combination with chemotherapy.

• Authors: Hui Li, Yang Yu, Yanling Zhao, Deanna Wu, Xiaoman Yu, Jiaxiong Lu, Zhenghu Chen, Huiyuan Zhang, Yongguang Hu, Yuanfen Zhai, Jun Su, Ayinuer Aheman, Augusto De Las Casas, Jingling Jin, Xin Xu, Zhongcheng Shi, Sarah E Woodfield, Sanjeev A Vasudevan, Saurabh Agarwal, Yusheng Yan, Jianhua Yang, Jennifer H Foster
• Journal: Cancer letters (Cancer Lett) Vol. 457 Pg. 129-141 (08 10 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 31100410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Quinazolines
• agerafenib
• Doxorubicin
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• Drug Synergism
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Female
• Humans
• Mice, Nude
• Mice, Transgenic
• N-Myc Proto-Oncogene Protein (genetics)
• Neuroblastoma (drug therapy, enzymology, genetics, pathology)
• Phenylurea Compounds (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• Signal Transduction
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays