A Combination of EGFR/HER-2 and C-MET Inhibitors Reduced Cell Adhesion of Ovarian Cancer Clusters to the Extracellular Matrix (ECM)

Advanced ovarian cancer cell clusters, aggregates and spheroids are the primary source of cancer cells responsible for the metastatic spread that characterises advanced ovarian cancer. It is widely believed that the initial step in this metastatic process is the ability of ovarian cancer cells to adhere to the peritoneal surface, which is composed of a thin layer of mesothelial cells overlaying the basement membrane. Understanding the cellular events underlying this adhesion process could provide a means to prevent the widespread dissemination of ovarian cancer cells. This study aimed to investigate the role of the EGFR/HER-2/c-MET axis in the adhesion of ovarian cancer cell clusters and aggregates. Our results suggest that the adhesion of OVCAR-5 and SKOV-3 cell clusters/aggregates to ECM is growth factor-dependent and can be inhibited by the dual EGFR/HER inhibitor canertinib and the c-MET inhibitor PHA-665752. The combination of these inhibitors impaired cell adhesion, likely through disruption of the interaction between EGFR/HER-2/cMET and β4 integrins. These findings highlight the pivotal role of β4 integrins in the adhesion process of ovarian cancer cells and suggest that targeting this interaction may represent a potential therapeutic strategy to limit metastasis in advanced ovarian cancer.