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Introduction Clear cell ovarian cancer (CCOC) is a rare subtype of ovarian cancer. Response rate to first line chemotherapy is only 20%. When disease relapses, chemotherapy response rate is less than 10%. As a result, survival in advanced CCOC is poor and new therapies are urgently required. Upon binding its ligand, Hepatocyte Growth Factor (HGF), the receptor tyrosine kinase c- Met promotes ovarian cancer cell proliferation, survival and motility. c-Met has emerged as a major target and mediator of chemo-resistance in ovarian cancer. c-Met amplification has been demonstrated in 37% of CCOC, compared to 2.6% of epithelial cancers. Recent clinical trials with c-Met inhibitors in ovarian cancer showed response in only 20% of patients. More comprehensive understanding of c-Met signalling in CCOC is necessary to establish optimal therapeutic strategies. We have previously shown that c-Met transmits oncogenic signalling post-endocytosis and endocytosis inhibition reduces c-Met driven tumourigenesis. Consequently, manipulating c-Met endosomal signalling may provide a novel therapeutic approach in cancer treatment. c-Met endocytic trafficking has never previously been analysed in CCOC. Materials /Patients and methods Human tissue sections from CCOC patients were obtained via the Barts/UCLH Gynae Tissue Bank and underwent immunohistochemical staining for c-Met. CCOC cell lines - JHOC-5, JHOC-7, JHOC-9, OVTOKO, OVMANA - were investigated for c- Met expression, activation with exogenous HGF stimulation and downstream signalling via Western blot analysis. The effect of c-Met inhibitor PHA-665752 and siRNA knockdown of c-Met on cell viability was assessed using CellTiter-Glo. Cells were plated on coverslips and stimulated with HGF for 0 and 15 min, fixed and stained for c-Met and the endosomal marker EEA-1. Slides were imaged with fluorescent confocal microscopy. Results c-Met expression was observed in 5/6 patients CCOC patient samples when assessed by immunohistochemistry. Strong c-Met expression was seen at the cell surface of malignant epithelial cells but not in the stroma of these tumours. In our panel of CCOC cell lines, c-Met was found to be expressed with JHOC-5 cells expressing the highest levels. Stimulation of the cell lines with exogenous HGF activated c-Met and the downstream signals ERK1/2 and AKT, followed by degradation of c-Met. This activation was blocked by pre-treatment with c-Met inhibitors. The c-Met inhibitor PHA-665752 and siRNA knockdown significantly reduced the cell's viability (n=3 p<0.001). Exogenous HGF stimulation triggers rapid c-Met endocytosis in our cell panel. Blocking endocytosis with the dynamin inhibitor Dyngo reduced c-Met ERK1/2 and AKT signalling. Conclusion This study confirms c-Met as a therapeutic target in CCOC and illustrates, for the first time, that c-Met is endocytosed in CCOC. Further work is ongoing to unravel these pathways and to identify novel treatment approaches. [ABSTRACT FROM AUTHOR]