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Cellular Oncology
Published in: Cellular Oncology 4/2019

01-08-2019 | Erlotinib | Original paper

The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells

Authors: Majid Momeny, Fatemeh Esmaeili, Sepideh Hamzehlou, Hassan Yousefi, Sepehr Javadikooshesh, Vasimeh Vahdatirad, Zivar Alishahi, Seyedeh H. Mousavipak, Davood Bashash, Ahmad R. Dehpour, Seyyed M. Tavangar, Javad Tavakkoly-Bazzaz, Peiman Haddad, Farzaneh Kordbacheh, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Seyed H. Ghaffari

Published in: Cellular Oncology | Issue 4/2019

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Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells.

Methods

Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib.

Results

We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal.

Conclusions

Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.
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Metadata
Title
The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells
Authors
Majid Momeny
Fatemeh Esmaeili
Sepideh Hamzehlou
Hassan Yousefi
Sepehr Javadikooshesh
Vasimeh Vahdatirad
Zivar Alishahi
Seyedeh H. Mousavipak
Davood Bashash
Ahmad R. Dehpour
Seyyed M. Tavangar
Javad Tavakkoly-Bazzaz
Peiman Haddad
Farzaneh Kordbacheh
Kamran Alimoghaddam
Ardeshir Ghavamzadeh
Seyed H. Ghaffari
Publication date
01-08-2019
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 4/2019
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-019-00448-w

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Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
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