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

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.

• Authors: Adelina Plangger, Barbara Rath, Maximilian Hochmair, Martin Funovics, Christoph Neumayer, Robert Zeillinger, Gerhard Hamilton
• Journal: Investigational new drugs (Invest New Drugs) Vol. 40 Issue 2 Pg. 215-223 (04 2022) ISSN: 1573-0646 [Electronic] United States
• PMID: 34596822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Antineoplastic Agents
• Indoles
• Protein Kinase Inhibitors
• fascaplysine
• Afatinib
• EGFR protein, human
• ErbB Receptors
• CDK4 protein, human
• Cyclin-Dependent Kinase 4
• Cisplatin

Topics

• Afatinib (pharmacology, therapeutic use)
• Antineoplastic Agents (adverse effects)
• Carcinoma, Non-Small-Cell Lung (pathology)
• Cisplatin (therapeutic use)
• Cyclin-Dependent Kinase 4 (therapeutic use)
• ErbB Receptors
• Humans
• Indoles
• Lung Neoplasms (pathology)
• Mutation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)