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

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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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Acknowledgements

This study was financially supported by a grant from the Hematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Technical assistance of Ms. Azam Zaghal is gratefully acknowledged.

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Author notes

  1. Majid Momeny and Fatemeh Esmaeili contributed equally to this work.

Authors and Affiliations

  1. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland

    Majid Momeny

  2. Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Fatemeh Esmaeili, Sepideh Hamzehlou, Vasimeh Vahdatirad, Zivar Alishahi, Seyedeh H. Mousavipak, Kamran Alimoghaddam, Ardeshir Ghavamzadeh & Seyed H. Ghaffari

  3. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Sepideh Hamzehlou, Zivar Alishahi, Seyedeh H. Mousavipak & Javad Tavakkoly-Bazzaz

  4. Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Hassan Yousefi

  5. Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sepehr Javadikooshesh

  6. Department of Hematology and Blood Banking, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Davood Bashash

  7. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Ahmad R. Dehpour

  8. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Ahmad R. Dehpour

  9. Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Seyyed M. Tavangar

  10. Radiation Oncology Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran

    Peiman Haddad

  11. Cancer and Vascular Biology Group, ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia

    Farzaneh Kordbacheh

Authors
  1. Majid Momeny
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  2. Fatemeh Esmaeili
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  16. Ardeshir Ghavamzadeh
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  17. Seyed H. Ghaffari
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Contributions

M.M. designed the study; F.E., H.Y., S.J., Z.A., S.H.M., D.B. and F.K. conducted the research; A.R.D., S.M.T., J.T., P.H., K.A. and A.G. analyzed the data; M.M., S.H. and V.V. wrote the paper; M.M. and S.H.G. were primarily responsible for the final content. All authors have reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Majid Momeny or Seyed H. Ghaffari.

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Momeny, M., Esmaeili, F., Hamzehlou, S. et al. The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells. Cell Oncol. 42, 491–504 (2019). https://doi.org/10.1007/s13402-019-00448-w

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