Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells
| Autor: | Konecny, GE, Venkatesan, N, Yang, G, Dering, J, Ginther, C, Finn, R, Rahmeh, M, Fejzo, M Schoenberg, Toft, D, Jiang, S-W, Slamon, DJ, Podratz, KC |
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| Rok vydání: | 2008 |
| Předmět: |
EGFR
Oncology and Carcinogenesis Drug Screening Assays Cell Line ErbB-2 Uterine Cancer Antineoplastic Combined Chemotherapy Protocols Breast Cancer Humans Oncology & Carcinogenesis lapatinib skin and connective tissue diseases Extracellular Signal-Regulated MAP Kinases Protein Kinase Inhibitors Cancer Tumor Epidermal Growth Factor Antitumor HER2/neu Endometrial Neoplasms Oncogene Protein v-akt ErbB Receptors 5.1 Pharmaceuticals endometrial cancer Quinazolines Public Health and Health Services Female Development of treatments and therapeutic interventions Receptor Signal Transduction |
| Zdroj: | British journal of cancer, vol 98, iss 6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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