title: INC280, an orally available small molecule inhibitor of c-MET, reduces migration and adhesion in ovarian cancer cell models.
abstract: 5-year survival rates for ovarian cancer are approximately 40%, and for women diagnosed at late stage (the majority), just 27%. This indicates a dire need for new treatments to improve survival rates. Recent molecular characterization has greatly improved our understanding of the disease and allowed the identification of potential new targets. One such pathway of interest is the HGF/c-MET axis. Activation of the HGF/c-MET axis has been demonstrated in certain ovarian tumours, and been found to be associated with decreased overall survival, suggesting its potential as a therapeutic target. The objective of this study was to determine the efficacy of a novel, highly potent, orally-bioavailable c-MET inhibitor, INC280, in blocking cell phenotypes important in ovarian cancer metastasis. Using in vitro and ex vivo models, we demonstrate that INC280 inhibits HGF-induced c-MET, and reduces downstream signalling. HGF-stimulated chemotactic and random migration are decreased by INC280 treatment, to levels seen in non-stimulated cells. Additionally, HGF-induced adhesion of cancer cells to peritoneal tissue is significantly decreased by INC280 treatment. Overall, these data indicate that INC280 inhibits many cell behaviours that promote ovarian cancer metastasis, and merits further investigation as a therapeutic candidate in the treatment of patients with ovarian cancer.
authors.affiliation: 1] Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] St. Vincent's Clinical School, Faculty of Medicine, UNSW Australia, NSW, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Moran-Jones
authors.affiliation: Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Brown
authors.affiliation: 1] Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW, Australia [2] St. Vincent's Clinical School, Faculty of Medicine, UNSW Australia, NSW, Australia.
authors.forename: Goli
authors.initials: G
authors.lastname: Samimi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006801:Humans; D007093:Imidazoles; D020128:Inhibitory Concentration 50; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014227:Triazines
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; C066855:HGF protein, human; D007093:Imidazoles; D014227:Triazines; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C000613976:capmatinib