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

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-smallcell 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.

Preferential killing of p53-deficient cancer cells by reversine

“…48 As an example, the combination of several tyrosine kinase inhibitors with different specificities, as well as elevated concentrations of a single compound, reportedly lead to a rapid collapse of the tyrosine kinase network, resulting in efficient cell killing. 49 What are the mechanisms through which the inactivation of p53 augments the susceptibility of cancer cells to the cytotoxic effects of high-dose reversine? Based on our observations, it is tempting to hypothesize that the preferential cytotoxicity of high-dose reversine for p53-deficient cells might be intimately linked to specific cell cycle aberrations, in turn resulting from the deregulation of cell cycle checkpoints.…”

A novel multi‐kinase inhibitor pazopanib suppresses growth of synovial sarcoma cells through inhibition of the PI3K‐AKT pathway

“…[10][11][12][13] We therefore first asked whether pazopanib can act directly to inhibit the proliferation of synovial sarcoma cells. As shown in Figure 1A, pazopanib showed dose-dependent growth inhibition in all synovial sarcoma cell lines examined in the current study.…”

“…Although pazopanib has been developed and is currently being clinically used as an anti-angiogenesis agent, 8,20 direct antitumor effects of pazopanib have been described in the published literature for several tumor cells, including, multiple myeloma, 10 HER2 þ breast cancer, 11 lung cancer, 12 and chronic lymphocytic leukemia cells. 13 The dose-effectiveness of pazopanib against synovial sarcoma cells in the present study was comparable to the results of these studies which showed an IC 50 value ranging between approximately 2 and 15 mg/ml.…”

Identifying Protein-protein Interaction Sites Using Peptide Arrays

“…For example: the FLT3 kinase, which is related to acute myeloid leukemia, phosphorylates Tyr-containing substrate peptides found by a peptide array screening 6 . The inhibitory properties of the tyrosine kinase inhibitors pazopanib and lapatinib was tested using peptide array screening 23 . Peptides array can be used to identify the sites that mediate protein-protein interactions.…”