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04, 2022;40 (2): 215-223.

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

Adelina Plangger, Barbara Rath, Maximilian Hochmair, Martin Funovics, Christoph Neumayer, Robert Zeillinger, Gerhard Hamilton
Author Information
  1. Adelina Plangger: Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
  2. Barbara Rath: Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
  3. Maximilian Hochmair: Department of Respiratory & Critical Care Medicine, Karl Landsteiner Institute of Lung Research & Pulmonary Oncology, Vienna, Austria.
  4. Martin Funovics: Division of Cardiovascular and Interventional Radiology, Department of Biomedical Imaging and Image-Guided Therapy Medical, University of Vienna, Vienna, Austria.
  5. Christoph Neumayer: Department of Vascular Surgery, Medical University of Vienna, Vienna, Austria.
  6. Robert Zeillinger: Molecular Oncology Group, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
  7. Gerhard Hamilton: Institute of Pharmacology, Medical University of Vienna, Vienna, Austria. gerhard.hamilton@meduniwien.ac.at. ORCID
PMID: 34596822 DOI: 10.1007/s10637-021-01181-8

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.

Keywords

Afatinib Cytotoxicity Fascaplysin Non-small cell lung cancer Pleural effusion Protein phosphorylation

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MeSH Term

Afatinib
Antineoplastic Agents
Carcinoma, Non-Small-Cell Lung
Cisplatin
Cyclin-Dependent Kinase 4
ErbB Receptors
Humans
Indoles
Lung Neoplasms
Mutation
Protein Kinase Inhibitors

Chemicals

Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
fascaplysine
Afatinib
EGFR protein, human
ErbB Receptors
CDK4 protein, human
Cyclin-Dependent Kinase 4
Cisplatin
Journal Article Research Support, Non-U.S. Gov't

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