Moran-Jones, Kim, Brown, Laura M and Samimi, Goli (2015) INC280, an orally available small molecule inhibitor of c-Met, reduces migration and adhesion in ovarian cancer cell models. Scientific Reports.

Abstract

Overall 5-year survival rates for ovarian cancer have remained stable at only 40% for more than two decades. Furthermore, women diagnosed at late stage, who make up a majority of ovarian cancer patients, carry 5-year survival rates of just 27%. These figures indicate a dire need for new therapeutic treatments to help improve survival rates in ovarian cancer. Recent advances in molecular and histological characterization of ovarian cancer have greatly improved our understanding of the disease and have allowed the identification of potential new targets. Although no targeted therapies are currently approved for treatment of ovarian cancer, a pathway of interest is the HGF/c-Met axis. Activation of the HGF/c-Met axis has been demonstrated in certain ovarian tumors, and has 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 behaviors important in ovarian cancer metastasis. Using in vitro and ex vivo models, we demonstrate that INC280 inhibits HGF-induced c-Met phosphorylation for at least 48 hours, and reduces downstream signaling via ERK and Akt. Both chemotactic and random migration are decreased by INC280 treatment, to levels seen in non-stimulated cells. In addition, HGF-induced adhesion to peritoneal tissue is also significantly decreased by INC280 treatment. Overall, these data indicate that INC280 inhibits many cell behaviors that promote ovarian cancer metastasis, and merits further investigation as a therapeutic candidate in the treatment of patients with ovarian cancer.

Item Type:	Article
Date Deposited:	02 May 2016 23:45
Last Modified:	02 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/21401