1. ¹INSERM, U848, Villejuif, France
2. ²Institut Gustave Roussy, Villejuif, France
3. ³Laboratoire de Recherche Translationnelle, Institut Gustave Roussy, Villejuif, France
4. ⁴Université Paris-Sud XI, Paris, France
5. ⁵Unité de Génomique fonctionnelle et Bioinformatique, Institut Gustave Roussy, Villejuif, France
6. ⁶Department of Medicine, Institut Gustave Roussy, Villejuif, France

Correspondence: Dr G Kroemer, INSERM, U848, Institut Gustave Roussy, 39 rue Camille Desmoulins, F-94805, Villejuif, France. E-mail: kroemer@igr.fr

⁷These authors contributed equally to this work.

⁸These authors share senior co-authorship.

Received 17 April 2009; Revised 8 July 2009; Accepted 8 August 2009; Published online 14 September 2009.

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.