Abstract 5311: Studies of co-expression of cancer stem cell markers and growth factor receptors in human ovarian cancer cells and their responses to treatment with various tyrosine kinase inhibitors

Abstract

Abstract Ovarian cancer remains one of the most lethal types of gynaecological cancer. There is an urgent need for the identification of biomarkers for use in the early detection of such cancers and for predicting the response to therapy. Here, we investigated the sensitivity in vitro of a panel of human ovarian cancer cell lines to treatment with several small molecules tyrosine kinase inhibitors (TKIs) including reversible EGFR (Gefitinib), reversible dual EGFR/HER-2 (Lapatinib), reversible pan-ErbB family (Sapatinib), irreversible dual EGFR/HER-2 (Canertinib, Neratinib), the irreversible ErbB family blocker (Afatinib), as well as v-abl/src/C-kit (Dasatinib) and v-abl/C-kit/PDGFR TKI (Imatinib). We also determined the expression of putative ovarian cancer stem cell (CSC) markers (e.g. CD24, CD44, CD117), P-Glycoprotein (Pgp), and HER family members on this panel of cancer cells by FACS analysis and whether there was any correlation between the expression of these biomarkers and response to treatment with these agents. Of the CSC markers, the expression of CD24 was high in five of the ten ovarian cancer cell lines examined, and with MFI values ranging from of 450 (SKOV3) to 24 (SW626). In contrast, the CD24 negative ES2 cells had the highest level of expression of CD44 (MFI = 977). The MFI values for other CD44 positive tumours ranged from 139.51 (PA1) to 46.38 (Caov3). All ovarian cancer cells used in this study were negative for the expression of both CD117 and Pgp and overexpression of HER-2 (MFI = 368) was only detected in the EGFR positive SKOV3 cells. Of the pan-HER family TKIs, afatinib inhibited the growth of ovarian cancer cells with IC50 values ranging from 83nM (Caov3) to 1.40μM (ES2) and sapatinib inhibited the growth with IC50 values ranging from 24nM (Caov3) to 4.41μM (PA1) respectively. Of the two irreversible dual EGFR/HER-2 TKIs, neratinib was more effective than canertinib at inhibiting the growth of ovarian cancer cells. In contrast, Gefitinib and Lapatinib were the most effective drugs at inhibiting the growth of CaoV3 and SKOV3 cells, with IC50 values of 1.8nM and 1.4nM respectively. Interestingly, the majority of ovarian cancer cells were highly sensitive to treatment with dasatinib with IC50 values of below 3.0nM but were relatively resistant to treatment with imatinib (i.e. IC50>10μM). With the exceptions of correlation between the CD24/HER-2 co-expression and response to gefitinib and lapatinib, there was no statistically significant correlation between the expression of CD24, CD44, EGFR, HER-2 or other combinations of these markers and response to other agents. Our results support the need for further investigation of the predictive value of CD24/HER-2 co-expression, and the therapeutic potential of dasatinib when used in combination with the HER inhibitors in ovarian cancer. Citation Format: Soozana Puvanenthiran, Sharadah essapen, Alan Michael Seddon, Helmout Modjtahedi. Studies of co-expression of cancer stem cell markers and growth factor receptors in human ovarian cancer cells and their responses to treatment with various tyrosine kinase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5311. doi:10.1158/1538-7445.AM2015-5311