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Cellular Oncology

, Volume 42, Issue 4, pp 491–504 | Cite as

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

  • Majid MomenyEmail author
  • 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. GhaffariEmail author
Original paper
  • 327 Downloads

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.

Keywords

Pancreatic ductal adenocarcinoma The ERBB family Dacomitinib Radio-sensitivity 

Notes

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.

Author 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.

Compliance with ethical standards

Competing interests

The authors declare no conflict of interest.

Supplementary material

13402_2019_448_MOESM1_ESM.docx (978 kb)
ESM 1 (DOCX 977 kb)

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Copyright information

© International Society for Cellular Oncology 2019

Authors and Affiliations

  • Majid Momeny
    • 1
    Email author
  • Fatemeh Esmaeili
    • 2
  • Sepideh Hamzehlou
    • 2
    • 3
  • Hassan Yousefi
    • 4
  • Sepehr Javadikooshesh
    • 5
  • Vasimeh Vahdatirad
    • 2
  • Zivar Alishahi
    • 2
    • 3
  • Seyedeh H. Mousavipak
    • 2
    • 3
  • Davood Bashash
    • 6
  • Ahmad R. Dehpour
    • 7
    • 8
  • Seyyed M. Tavangar
    • 9
  • Javad Tavakkoly-Bazzaz
    • 3
  • Peiman Haddad
    • 10
  • Farzaneh Kordbacheh
    • 11
  • Kamran Alimoghaddam
    • 2
  • Ardeshir Ghavamzadeh
    • 2
  • Seyed H. Ghaffari
    • 2
    Email author
  1. 1.Turku Centre for BiotechnologyUniversity of Turku and Åbo Akademi UniversityTurkuFinland
  2. 2.Hematology/Oncology and Stem Cell Transplantation Research CenterTehran University of Medical SciencesTehranIran
  3. 3.Department of Medical Genetics, School of MedicineTehran University of Medical SciencesTehranIran
  4. 4.Department of Biochemistry and Molecular BiologyLouisiana State University Health Sciences CenterNew OrleansUSA
  5. 5.Department of Medical GeneticsShahid Beheshti University of Medical SciencesTehranIran
  6. 6.Department of Hematology and Blood Banking, Faculty of Allied MedicineShahid Beheshti University of Medical SciencesTehranIran
  7. 7.Department of Pharmacology, School of MedicineTehran University of Medical SciencesTehranIran
  8. 8.Experimental Medicine Research CenterTehran University of Medical SciencesTehranIran
  9. 9.Department of Pathology, School of MedicineTehran University of Medical SciencesTehranIran
  10. 10.Radiation Oncology Research Center, Cancer InstituteTehran University of Medical SciencesTehranIran
  11. 11.Cancer and Vascular Biology Group, ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical ResearchThe Australian National UniversityCanberraAustralia

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