Lapatinib, a dual inhibitor of ErbB-1/-2 receptors, enhances effects of combination chemotherapy in bladder cancer cells

Lynsey A. McHugh, A. Emre Sayan, Jakob Mejlvang, T. R.Leyshon Griffiths, Yiyang Sun, Margaret M. Manson, Eugene Tulchinsky, J. Kilian Mellon, Marina Kriajevska

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Survival rate of patients diagnosed with the invasive form of bladder cancer is low suggesting an urgent need to implement novel treatments. GTC (gemcitabine, paclitaxel and cisplatin) is a new chemotherapeutic regimen, which has shown promise in clinical trials. Given that receptor tyrosine kinases of the ErbB family are overexpressed in a high proportion of metastatic bladder tumours, approaches involving small-molecule inhibitors of ErbB receptors in combination with conventional cytostatic drugs are of potential interest. Here, we show that the dual inhibitor of ErbB receptors, lapatinib, enhances cytostatic and induces cytotoxic effects of GTC in two bladder cancer cell lines which differ with regard to expression levels of proteins taking part in the ErbB pathway. Lapatinib inhibited phosphorylation of ErbB receptors and also reduced the level of phosphorylated AKT. Flow cytometry analysis demonstrated that GTC treatment affects cell cycle distribution differently in the presence or absence of lapatinib. In RT112 cells, which express high levels of ErbB receptors and harbour wild-type p53, combined GTC/lapatinib treatment resulted in the phosphorylation of p53 at Ser46 and accumulation of sub-G1 cell populations. Our data indicate that a combinatorial approach involving GTC and lapatinib may have therapeutic potential in a subset of bladder tumours depending on the genetic context.

Original languageEnglish
Pages (from-to)1155-1163
Number of pages9
JournalInternational Journal of Oncology
Volume34
Issue number4
DOIs
Publication statusPublished - Jul 3 2009
Externally publishedYes

Keywords

  • ErbB receptor
  • Gemcitabine
  • Lapatinib
  • Paclitaxel cisplatin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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