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

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 ( IC50 range: 0.052 - 10.9 mu mol). 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.