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Synergistic cytotoxicity of the CDK4 inhibitor Fascaplysin in combination with EGFR inhibitor Afatinib against Non-small Cell Lung Cancer.

Authors
  • Plangger, Adelina1
  • Rath, Barbara1
  • Hochmair, Maximilian2
  • Funovics, Martin3
  • Neumayer, Christoph4
  • Zeillinger, Robert5
  • Hamilton, Gerhard6
  • 1 Institute of Pharmacology, Medical University of Vienna, Vienna, Austria. , (Austria)
  • 2 Department of Respiratory & Critical Care Medicine, Karl Landsteiner Institute of Lung Research & Pulmonary Oncology, Vienna, Austria. , (Austria)
  • 3 Division of Cardiovascular and Interventional Radiology, Department of Biomedical Imaging and Image-Guided Therapy Medical, University of Vienna, Vienna, Austria. , (Austria)
  • 4 Department of Vascular Surgery, Medical University of Vienna, Vienna, Austria. , (Austria)
  • 5 Molecular Oncology Group, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria. , (Austria)
  • 6 Institute of Pharmacology, Medical University of Vienna, Vienna, Austria. [email protected] , (Austria)
Type
Published Article
Journal
Investigational New Drugs
Publisher
Springer-Verlag
Publication Date
Apr 01, 2022
Volume
40
Issue
2
Pages
215–223
Identifiers
DOI: 10.1007/s10637-021-01181-8
PMID: 34596822
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

In the absence of suitable molecular markers, non-small cell lung cancer (NSCLC) patients have to be treated with chemotherapy with poor results at advanced stages. Therefore, the activity of the anticancer marine drug fascaplysin was tested against primary NSCLC cell lines established from pleural effusions. Cytotoxicity of the drug or combinations were determined using MTT assays and changes in intracellular phosphorylation by Western blot arrays. Fascaplysin revealed high cytotoxicity against NSCLC cells and exhibit an activity pattern different of the standard drug cisplatin. Furthermore, fascaplysin synergizes with the EGFR tyrosine kinase inhibitor (TKI) afatinib to yield a twofold increased antitumor effect. Interaction with the Chk1/2 inhibitor AZD7762 confirm the differential effects of fascplysin and cisplatin. Protein phosphorylation assays showed hypophosphorylation of Akt1/2/3 and ERK1/2 as well as hyperphosphorylation of stress response mediators of H1299 NSCLC cells. In conclusion, fascaplysin shows high cytotoxicity against pleural primary NSCLC lines that could be further boosted when combined with the EGFR TKI afatinib. © 2021. The Author(s).

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