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Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

Oncogene volume 28, pages 4249–4260 (2009)Cite this article

Abstract

Pazopanib and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the VEGF tyrosine kinase receptors 1, 2 and 3 (pazopanib), and the HER1 and HER2 receptors in a dual manner (lapatinib). Pazopanib has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as PDGFR and c-kit. Here, we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non-small-cell lung cancer cells. Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases (such as c-Met) that were not or only partially affected by either of the two agents alone. We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells, some of which were specific for the combination of both agents. Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up- or downregulation reflected the combined action of pazopanib and lapatinib. Indeed, pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non-small-cell lung cancer cells as well as on unrelated carcinomas. Altogether, these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects. Such combinations may lead to a ‘collapse’ of pro-survival signal transduction pathways that leads to apoptotic cell death.

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Acknowledgements

GK received grants from Ligue Nationale contre le Cancer (équipe labellisée), Agence Nationale de Recherche, Institut National contre le Cancer, Cancéropôle Ile-de France, European Union (Active p53, ApoSys, ChemoRes, DeathTrain, RIGHT, TransDeath) and Fondation pour la Recherche Médicale.

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Author notes

  1. K A Olaussen and F Commo: These authors contributed equally to this work.

  2. J -C Soria and G Kroemer: These authors share senior co-authorship.

Authors and Affiliations

  1. INSERM, U848, Villejuif, France

    K A Olaussen, M Tailler, I Vitale, S Q Raza & G Kroemer

  2. Institut Gustave Roussy, Villejuif, France

    K A Olaussen, F Commo, M Tailler, L Lacroix, I Vitale, S Q Raza, J -C Soria & G Kroemer

  3. Laboratoire de Recherche Translationnelle, Institut Gustave Roussy, Villejuif, France

    K A Olaussen, F Commo, L Lacroix & J -C Soria

  4. Université Paris-Sud XI, Paris, France

    K A Olaussen, M Tailler, I Vitale, S Q Raza, J -C Soria & G Kroemer

  5. Unité de Génomique fonctionnelle et Bioinformatique, Institut Gustave Roussy, Villejuif, France

    C Richon, P Dessen & V Lazar

  6. Department of Medicine, Institut Gustave Roussy, Villejuif, France

    J -C Soria

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Correspondence to G Kroemer.

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Olaussen, K., Commo, F., Tailler, M. et al. Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines. Oncogene 28, 4249–4260 (2009). https://doi.org/10.1038/onc.2009.277

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