Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells

Majid Momeny,Fatemeh Esmaeili,Farinaz Barghi,Ghazaleh Zarrinrad,Ardeshir Ghavamzadeh,Ghazaleh Sankanian,Javad Tavakkoly Bazzaz ,Ahmad Reza Dehpour ,Kamran Alimoghaddam,Reza Ghasemi,Zahra Sabourinejad,Haniyeh Eyvani,Arash Poursheikhani,Bahram Chahardouli,Hassan Yousefi,Shahab Mirshahvaladi,Davood Bashash,Leila Dardaei,Farima Moghaddaskho,Azam Zaghal,Zivar Alishahi,Seyed H Ghaffari

doi:10.1038/s41598-017-04147-0

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination of EOC cells are the major reasons for low survival rate. Targeting signal transduction pathways which promote therapy resistance and metastatic dissemination is the key to successful treatment. Members of the ErbB family of receptors are over-expressed in EOC and play key roles in chemoresistance and invasiveness. Despite this, single-targeted ErbB inhibitors have demonstrated limited activity in chemoresistant EOC. In this report, we show that dacomitinib, a pan-ErbB receptor inhibitor, diminished growth, clonogenic potential, anoikis resistance and induced apoptotic cell death in therapy-resistant EOC cells. Dacominitib inhibited PLK1-FOXM1 signalling pathway and its down-stream targets Aurora kinase B and survivin. Moreover, dacomitinib attenuated migration and invasion of the EOC cells and reduced expression of epithelial-to-mesenchymal transition (EMT) markers ZEB1, ZEB2 and CDH2 (which encodes N-cadherin). Conversely, the anti-tumour activity of single-targeted ErbB agents including cetuximab (a ligand-blocking anti-EGFR mAb), transtuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small-molecule tyrosine kinase inhibitor) were marginal. Our results provide a rationale for further investigation on the therapeutic potential of dacomitinib in treatment of the chemoresistant EOC.

Highlights

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide
Using Tukey’s post hoc analysis, we found no difference in the expression of the ErbB family between the two groups of the EOC cells (Fig. 1A,B)
Data shown represent the mean ± standard deviation (SD) from three independent experiments, each performed in triplicate

Summary

Introduction

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination of EOC cells are the major reasons for low survival rate. Members of the ErbB family of receptors are overexpressed in EOC and play key roles in chemoresistance and invasiveness. Single-targeted ErbB inhibitors have demonstrated limited activity in chemoresistant EOC. Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related death among women worldwide and accounts for the highest mortality rate of all gynaecological malignancies. The ErbB or epidermal growth factor (EGF) family of receptor tyrosine kinases consists of four closely related members including EGFR, HER2, HER3 and HER47. This family plays key roles in tumour growth, metastasis and therapy resistance through activation of down-stream pathways such as Ras/MAPK and PI3K/AKT8, 9. HER3 is up-regulated in EOC clinical samples which correlates with a worse prognosis[18, 19]

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Conclusion