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The Erbb Receptor Inhibitor Dacomitinib Suppresses Proliferation and Invasion of Pancreatic Ductal Adenocarcinoma Cells Publisher Pubmed



Momeny M1 ; Esmaeili F2 ; Hamzehlou S2, 3 ; Yousefi H4 ; Javadikooshesh S5 ; Vahdatirad V2 ; Alishahi Z2, 3 ; Mousavipak SH2, 3 ; Bashash D6 ; Dehpour AR7, 8 ; Tavangar SM9 ; Tavakkolybazzaz J3 ; Haddad P10 ; Kordbacheh F11 Show All Authors
Authors
  1. Momeny M1
  2. Esmaeili F2
  3. Hamzehlou S2, 3
  4. Yousefi H4
  5. Javadikooshesh S5
  6. Vahdatirad V2
  7. Alishahi Z2, 3
  8. Mousavipak SH2, 3
  9. Bashash D6
  10. Dehpour AR7, 8
  11. Tavangar SM9
  12. Tavakkolybazzaz J3
  13. Haddad P10
  14. Kordbacheh F11
  15. Alimoghaddam K2
  16. Ghavamzadeh A2
  17. Ghaffari SH2
Show Affiliations
Authors Affiliations
  1. 1. Turku Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland
  2. 2. Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
  5. 5. Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  6. 6. Department of Hematology and Blood Banking, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  7. 7. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  8. 8. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
  9. 9. Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  10. 10. Radiation Oncology Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
  11. 11. Cancer and Vascular Biology Group, ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, ACT, Australia

Source: Cellular Oncology Published:2019


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. © 2019, International Society for Cellular Oncology.
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