Novel multi-targeted ErbB family inhibitor afatinib blocks EGF-induced signaling and induces apoptosis in neuroblastoma.

Xinfang Mao,Fuchun Zhang,Sanjeev A Vasudevan,Huiyuan Zhang,Sarah E Woodfield,Yang Yu,Ling Tao,Jonathan C Pang,Zhenghu Chen,Shan Guan,Yanling Zhao,Jiaxiong Lu,Jianhua Yang

doi:10.18632/oncotarget.13657

Abstract

Neuroblastoma is the most common extracranial solid tumor in children. The ErbB family of proteins is a group of receptor tyrosine kinases that promote the progression of various malignant cancers including neuroblastoma. Thus, targeting them with small molecule inhibitors is a promising strategy for neuroblastoma therapy. In this study, we investigated the anti-tumor effect of afatinib, an irreversible inhibitor of members of the ErbB family, on neuroblastoma. We found that afatinib suppressed the proliferation and colony formation ability of neuroblastoma cell lines in a dose-dependent manner. Afatinib also induced apoptosis and blocked EGF-induced activation of PI3K/AKT/mTOR signaling in all neuroblastoma cell lines tested. In addition, afatinib enhanced doxorubicin-induced cytotoxicity in neuroblastoma cells, including the chemoresistant LA-N-6 cell line. Finally, afatinib exhibited antitumor efficacy in vivo by inducing apoptosis in an orthotopic xenograft neuroblastoma mouse model. Taken together, these results show that afatinib inhibits neuroblastoma growth both in vitro and in vivo by suppressing EGFR-mediated PI3K/AKT/mTOR signaling. Our study supports the idea that EGFR is a potential therapeutic target in neuroblastoma. And targeting ErbB family protein kinases with small molecule inhibitors like afatinib alone or in combination with doxorubicin is a viable option for treating neuroblastoma.

Highlights

Neuroblastoma (NB) is a pediatric cancer deriving from neural crest and is commonly found in the adrenal medulla or along the sympathetic chain [1]
Epidermal growth factor receptor (EGFR) is present in many tumors from NB patients and is rarely mutated [35,36,37]
A novel EGFR extracellular domain deletion mutant EGFRΔ768 has been found in primary tumors of NB patients and in a NB cell line BE2M17, which confers an aggressive cancer phenotype in NB cells www.impactjournals.com/oncotarget

Summary

Introduction

Neuroblastoma (NB) is a pediatric cancer deriving from neural crest and is commonly found in the adrenal medulla or along the sympathetic chain [1]. The ErbB family of RTKs, which consist of Epidermal growth factor receptor (EGFR) (ErbB1 or HER1), ErbB2 (HER2 or Neu), ErbB3 (HER3), and ErbB4 (HER4), have been shown to promote tumor progression in various cancer types [7]. EGFR is a transmembrane tyrosine kinase receptor that binds to ligands like Epidermal growth factor (EGF) and Transforming growth factor alpha (TGF-α) through its extracellular domain to activate downstream signaling pathways [15, 16]. These pathways include PI3K/AKT/ mTOR pathway, which is critical for cell survival and proliferation, as well as, the KRAS/BRAF/MEK/ERK, and JAK2/STAT3 pathways [7, 17, 18]. Previous studies have identified EGFR as a potential therapeutic target in NB [21] and pan-ErbB inhibition is a therapeutic option for treating NB patients [20], which supports further study of the efficacy of ErbB family inhibitors in NB

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Results

Conclusion