title: Dacomitinib (PF-00299804), a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor, demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro.
abstract: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that carries an extremely poor prognosis. Up to 35 % of USC may overexpress the epidermal growth factor receptor-2 (HER2/neu) at strong (i.e., 3+) level by immunohistochemistry (IHC) or harbor HER2/neu gene amplification by fluorescence in situ hybridization (FISH). In this study, we assessed the sensitivity of a panel of USC cell lines with and without HER2/neu gene amplification to dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor tyrosine kinase inhibitor. Eight primary cell lines (i.e., four harboring HER2/neu gene amplification by FISH and four FISH- cell lines), all demonstrating similar in vitro growth rates, were evaluated in viability/proliferation assays. The effect of dacomitinib on cell growth, cell cycle distribution, and signaling was determined using flow cytometry-based assays. Dacomitinib caused a significantly stronger growth inhibition in HER2/neu FISH+ USC cell lines when compared to FISH- USC (dacomitinib half maximal inhibitory concentration (IC50) mean ± SEM = 0.02803 ± 0.003355 μM in FISH+ versus 1.498 ± 0.2209 μM in FISH- tumors, P < 0.0001). Dacomitinib growth inhibition was associated with a significant and dose-dependent decline in phosphorylated HER2/neu and S6 transcription factor and a dose-dependent and time-dependent cell cycle arrest in G0/G1 in FISH+ USC. Dacomitinib is remarkably effective against chemotherapy-resistant HER2/neu gene-amplified USC. Clinical studies with dacomitinib in HER2/neu FISH+ USC patients resistant to standard salvage chemotherapy are warranted.
authors: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors: Liancheng
authors: L
authors: Zhu
authors: Salvatore
authors: S
authors: Lopez
authors: Stefania
authors: S
authors: Bellone
authors: Jonathan
authors: J
authors: Black
authors: Emiliano
authors: E
authors: Cocco
authors: Tiffany
authors: T
authors: Zigras
authors: Federica
authors: F
authors: Predolini
authors: Elena
authors: E
authors: Bonazzoli
authors: Beatrice
authors: B
authors: Bussi
authors: Zachary
authors: Z
authors: Stuhmer
authors: Carlton L
authors: CL
authors: Schwab
authors: Diana P
authors: DP
authors: English
authors: Elena
authors: E
authors: Ratner
authors: Dan-Arin
authors: DA
authors: Silasi
authors: Masoud
authors: M
authors: Azodi
authors: Peter E
authors: PE
authors: Schwartz
authors: Thomas J
authors: TJ
authors: Rutherford
authors: Alessandro D
authors: AD
authors: Santin
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D052999:Quinazolinones / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C525726:dacomitinib; C508053:ERBB2 protein, human