Elevated expression of epidermal growth factor receptor (EGFR) and Her-2 has been shown to correlate with poor survival outcomes in women with ovarian cancers. Gefitinib (EGFR inhibitor) and canertinib (EGFR/Her-2 inhibitor) were studied in clinical trials with recurrent and refractory ovarian cancers, but clinical responses were limited. Therefore, the use of anti-EGFR inhibitors was not considered the frontline treatment in ovarian cancers. Advanced ovarian cancers often cause the accumulation of body fluid (ascites) in the abdominal cavity. Ascites carrying ovarian cancer cells is a main route of cancer cell metastasis. Therefore, inhibition of ascitic ovarian cancer may reduce the metastatic potential and secondary growth.
We are particularly interested in growth inhibition by gefitinib and canertinib in ascitic ovarian cancer cells. We hypothesized that ovarian cancer cells that over-expressed EGFR and Her-2 were susceptible to gefitinib and canertinib. Therefore, the cells would exhibit significant reduction in the growth and survival in the presence of the drugs compared with cancer cells that had low expressions of the protein receptors. OVCAR-5, SKOV-3, and OVCAR-4 cell lines were cultured in culture plates with non-adherent surface to mimic ascitic ovarian cancer cells. Cancer cells were exposed to inhibitors for 48 hours. Cell proliferation, apoptosis, glucose uptake, activation of EGFR, Her-2, Akt, Erk, and cell adhesion were investigated. Results showed that gefitinib and canertinib significantly inhibited cell growth. Canertinib was a more potent inhibitor than gefitinib for reduction of proliferation, glucose uptake and adhesion, and canertinib induced an increase of apoptosis in SKOV-3 cell line. The responses to gefitinib and canertinib were strongly associated with elevated expression of EGFR and Her-2.
In conclusion, we suggest that targeting both EGFR and Her-2 can produce profound inhibitory effects in ascitic ovarian cancer. In addition, pre-screening the status of EGFR/Her-2 expression in a patient is essential to obtain clinical benefits from anti-EGFR inhibitors.