Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells

Br J Cancer. 2008 Mar 25;98(6):1076-84. doi: 10.1038/sj.bjc.6604278. Epub 2008 Mar 11.


In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent manner. Sensitive cell lines also exhibited increased expression of EGFR ligands or HER3. In contrast, lapatinib-resistant cell lines exhibited high androgen receptor (AR) levels or epithelial-to-mesenchymal transition (post-EMT) features. In endometrial cancer cells, at a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for lapatinib plus carboplatin, paclitaxel, docetaxel, and doxorubicin. These observations provide a clear biologic rational to test lapatinib as a single agent or in combination with chemotherapy in endometrial cancer with HER2 overexpression. Expression of EGFR, its ligands, HER3, AR, and post-EMT markers warrant further evaluation to help define patients with HER2-nonoverexpressing endometrial cancer most likely to benefit from lapatinib.

Publication types

  • Evaluation Study

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Endometrial Neoplasms / drug therapy*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Lapatinib
  • Oncogene Protein v-akt / metabolism
  • Protein Kinase Inhibitors / therapeutic use*
  • Quinazolines / administration & dosage
  • Quinazolines / therapeutic use*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction / drug effects


  • Protein Kinase Inhibitors
  • Quinazolines
  • Lapatinib
  • EGFR protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Oncogene Protein v-akt
  • Extracellular Signal-Regulated MAP Kinases