Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma

Our plain-English summary of Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma, by R. Tranchant, L. Quetel, F. Montagne, et al (Lung Cancer, 2018).

The study

• Authors: R. Tranchant, L. Quetel, F. Montagne, J. De Wolf, C. Meiller, L. De Koning, F. Le Pimpec-Barthes, J. Zucman-Rossi, M.C. Jaurand, D. Jean
• Journal: Lung Cancer
• Published: 2018;126:15-24
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive tumor with limited therapeutic options, requiring the development of efficient targeted therapies based on molecular phenotype of the tumor and to identify predictive biomarkers of the response.

Materials And Methods: The effect of inhibitors was investigated by cell viability assessment on primary MPM cell lines established in our laboratory from patient tumors, well characterized at the molecular level. Effects on apoptosis, cell proliferation and viability on MPM growing in multicellular spheroid were also assessed for verteporfin. Gene and protein expression, and gene knockdown by RNA interference were used to define mechanism of inhibition and specific predictive biomarkers.

Results: Anti-tumor effect of eight major signaling pathways inhibitors involved in mesothelial carcinogenesis was investigated. Three inhibitors were more efficient than cisplatin, the drug used as first-line chemotherapy in patients with MPM: verteporfin, a putative YAP inhibitor, defactinib, a FAK inhibitor and NSC668394, an Ezrin inhibitor. Verteporfin, the most efficient inhibitor, induced cell proliferation arrest and cell death, and is effective on 3D spheroid multicellular model. Verteporfin sensitivity was YAP-independent and related to molecular classification of the tumors. Biomarkers based on gene expression were identified to predict accurately sensitivity to these three inhibitors.

Conclusion: Our study shows that drug screening on well-characterized MPM cells allows for the identification of novel potential therapeutic strategies and defining specific biomarkers predictive of the drug response.

Copyright © 2018 Elsevier B.V. All rights reserved.

In plain English

This was a laboratory study of mesothelioma cells grown in dishes. It did not study people or asbestos exposure. The authors tested eight drugs that block cell signaling pathways, plus the chemotherapy drug cisplatin, on primary malignant pleural mesothelioma cell lines that they grew from patient tumors in their own laboratory: 33 cell lines in all, with 19 to 30 tested per drug. Three drugs, verteporfin, defactinib and NSC668394, reduced cell survival more than cisplatin did. Saracatinib, trametinib and galunisertib had no effect or only a slight effect in most cell lines. Cells from the C1 molecular group were more sensitive to verteporfin than cells from the C2 group, on two measures of drug response (P = 0.01 and P = 0.03). The effect of verteporfin did not appear to depend on YAP, the protein it is thought to block. The authors found gene-expression markers linked to sensitivity to each of the three drugs. The authors concluded that the three drugs were more efficient than cisplatin in these cells. They stated that the markers still need to be validated on patient tumor samples.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (cell culture) study testing drugs on mesothelioma cell lines, with gene and protein expression analyses and gene knockdown experiments
• Who was studied: 33 primary malignant pleural mesothelioma (MPM) cell lines established in the authors' laboratory from patient tumors; 19 to 30 cell lines were tested per drug
• Exposure: Eight signaling pathway inhibitors (verteporfin, defactinib, NSC668394, vandetanib, PD166866, saracatinib, trametinib, galunisertib) and cisplatin, given at a range of concentrations for 48 hours. Asbestos exposure was not studied.
• Main results:
  • Verteporfin, NSC668394 and defactinib had the highest effect on cell viability and were more efficient than cisplatin across the cell lines tested
  • Saracatinib, trametinib and galunisertib produced no decrease or only a slight decrease in cell viability in most cell lines
  • Vandetanib and PD166866 had an effect on some cell lines, but their overall efficacy was lower than cisplatin
  • Cell lines in the C1 molecular group were significantly more sensitive to verteporfin than C2 cell lines, measured by AUC (P = 0.01) and by GI50 (P = 0.03)
  • Sensitivity to NSC668394 and to defactinib was not related to molecular classification or mutational profile
  • After verteporfin treatment, 78.4% of cells in a sensitive cell line and 32.7% in a resistant cell line were dead
  • In nine cell lines, switching off the YAP1 gene reduced cell viability by 12% to 45%, but this did not correlate with verteporfin sensitivity
  • The ratio of expression of two genes, MOK and SLC9A3R1, gave the best correlation with verteporfin sensitivity (r = 0.72; P = 0.0002)
  • Sensitivity to NSC668394 correlated with the level of Ezrin gene and protein expression
  • In epithelioid MPM cell lines only, defactinib response correlated with FAK protein expression (r = -0.59; P = 0.008) and FAK phosphorylation (r = -0.67; P = 0.010)
  • Expression of the LUM gene showed the strongest correlation with defactinib sensitivity, in all cell lines and in epithelioid cell lines
• The authors' conclusion: The authors concluded that verteporfin, defactinib and NSC668394 were more efficient than cisplatin in MPM cells. They concluded that verteporfin sensitivity is linked to the C1/C2 molecular classification and that verteporfin could be a potent anti-cancer drug for C1-group MPM. They also concluded that gene-expression biomarkers could predict sensitivity to these three inhibitors.
• Limitations the authors state:
  • The predictive biomarkers still need to be validated on patient tumor samples from clinical trials
  • The drugs were compared only with cisplatin alone, not with the standard cisplatin/pemetrexed combination
  • How NSC668394 works is not yet understood
  • Some screening results were discarded because they could not be reproduced

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, Apoptosis, Carcinogenesis, Cisplatin, Chemotherapy.

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