title: Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA.
authors.forename: G E
authors.initials: GE
authors.lastname: Konecny
authors.forename: N
authors.initials: N
authors.lastname: Venkatesan
authors.forename: G
authors.initials: G
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Dering
authors.forename: C
authors.initials: C
authors.lastname: Ginther
authors.forename: R
authors.initials: R
authors.lastname: Finn
authors.forename: M
authors.initials: M
authors.lastname: Rahmeh
authors.forename: M Schoenberg
authors.initials: MS
authors.lastname: Fejzo
authors.forename: D
authors.initials: D
authors.lastname: Toft
authors.forename: S-W
authors.initials: SW
authors.lastname: Jiang
authors.forename: D J
authors.initials: DJ
authors.lastname: Slamon
authors.forename: K C
authors.initials: KC
authors.lastname: Podratz
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051058:Oncogene Protein v-akt / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000077341:Lapatinib; D051058:Oncogene Protein v-akt; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human