title: A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth.
abstract: Elevated serum levels of hepatocyte growth factor (HGF) and high tumor expression of c-Met are both indicators of poor overall survival from ovarian cancer (OVCA). In the present study, we evaluated the role of the HGF signaling pathway in OVCA cell line chemoresistance and OVCA patient overall survival as well as the influence of HGF/c-Met signaling inhibition on the sensitivity of OVCA cells to combinational carboplatin plus paclitaxel therapy. The prevalence of the HGF receptor, c-Met, was determined by immunohistochemistry in primary OVCA samples (n=79) and OVCA cell lines (n=41). The influence of the c-Met-specific inhibitor MK8033 on OVCA cell sensitivity to combinations of carboplatin plus paclitaxel was examined in a subset of OVCA cells (n=8) by CellTiter-Blue cell viability assays. Correlation tests were used to identify genes associated with response to MK8033 and carboplatin plus paclitaxel. Identified genes were evaluated for influence on overall survival from OVCA using principal component analysis (PCA) modeling in an independent clinical OVCA dataset (n=218). Immunohistochemistry analysis indicated that 83% of OVCA cells and 92% of primary OVCA expressed the HGF receptor, c-Met. MK8033 exhibited significant anti-proliferative effects against a panel of human OVCA cell lines. Combination index values determined by the Chou-Talalay isobologram equation indicated synergistic activity in combinations of MK8033 and carboplatin plus paclitaxel. Pearson's correlation identified a 47-gene signature to be associated with MK8033-carboplatin plus paclitaxel response. PCA modeling indicated an association of this 47-gene response signature with overall survival from OVCA (P=0.013). These data indicate that HGF/c-Met pathway signaling may influence OVCA chemosensitivity and overall patient survival. Furthermore, HGF/c-Met inhibition by MK8033 represents a promising new therapeutic avenue to increase OVCA sensitivity to carboplatin plus paclitaxel.
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Marchion
authors.forename: Elona
authors.initials: E
authors.lastname: Bicaku
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiong
authors.forename: Nadim
authors.initials: N
authors.lastname: Bou Zgheib
authors.forename: Entidhar
authors.initials: E
authors.lastname: Al Sawah
authors.forename: Xiaomang Ba
authors.initials: XB
authors.lastname: Stickles
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Judson
authors.forename: Alex S
authors.initials: AS
authors.lastname: Lopez
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cubitt
authors.forename: Jesus
authors.initials: J
authors.lastname: Gonzalez-Bosquet
authors.forename: Robert M
authors.initials: RM
authors.lastname: Wenham
authors.forename: Sachin M
authors.initials: SM
authors.lastname: Apte
authors.forename: Anders
authors.initials: A
authors.lastname: Berglund
authors.forename: Johnathan M
authors.initials: JM
authors.lastname: Lancaster
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001567:Benzocycloheptenes / Q000008:administration & dosage / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001567:Benzocycloheptenes; C066855:HGF protein, human; D013449:Sulfonamides; C581209:1-(3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo(4,5)cyclohepta(1,2-b)pyridin-7-yl)-N-(pyridin-2-ylmethyl)methanesulfonamide; D017228:Hepatocyte Growth Factor; D016190:Carboplatin; D019859:Proto-Oncogene Proteins c-met; D017239:Paclitaxel