INC280, an orally available small molecule inhibitor of c-MET, reduces migration and adhesion in ovarian cancer cell models.

Kim Moran-Jones,Laura M Brown,Goli Samimi

doi:10.1038/srep11749

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.

Highlights

Suggesting an involvement of this pathway in ovarian development and proliferation[7]
While addition of HGF resulted in phosphorylation of AKT and ERK1/2, this activation was reduced upon treatment with INC280 (Fig. 1C), indicating inhibition of the c-MET downstream pathways PI3K and ERK/MAPK
Ovarian cancer is responsible for 1 in 20 cancer-related deaths in women in the USA1, and the stagnation in survival rates over the past 2 decades indicate a need for improved therapeutics

Summary

Introduction

Suggesting an involvement of this pathway in ovarian development and proliferation[7]. A number of c-MET inhibitors and HGF antagonists are currently under investigation, in both pre-clinical models of ovarian cancer, and clinical trials for multiple cancer types (reviewed in[6] and[19]). Some are specific for c-MET, while others exhibit activity against several tyrosine kinase receptors (reviewed in[6,19]) Many of these agents have been tested in pre-clinical models of ovarian cancer including PF-2341066 (c-MET-specific), Foretinib (c-MET and VEGFR-2), MK8033 (c-MET specific), DCC-2701 (c-MET/Tie-2/VEGFR-2), and SU11274 (c-MET specific) and lead to decreased cell motility and invasion, reduced adhesion and peritoneal dissemination, as well as reductions in tumour burden in treated cells and animals[20,21,22,23,24]. We investigate the effect of INC280 in a number of ovarian cancer cell models, and demonstrate decreases in activation of downstream signalling pathways, migration, and peritoneal adhesion

Objectives

Methods

Results

Conclusion