Abstract 4514: Studies on growth response of a panel of human ovarian tumor cell lines to treatment with afatinib, erlotinib, crizotinib and cytotoxic drugs

Abstract

Abstract Ovarian cancer is one of the most aggressive and fatal types of gynaecological cancer. To reduce mortality, it is considered important to discover the underlying molecular mechanisms and various cell signalling pathways which are altered in ovarian cancer. This study investigated the sensitivity of a panel of human ovarian cancer cell lines (OVCAR3, SKOV3, CAOV3, COV318, ES2, PA1, SW626, A2780, A2780CIS and A2780ADR) to treatment with the irreversible ErbB family blocker afatinib, the reversible EGFR tyrosine kinase inhibitor (TKI) erlotinib, the c-MET and Anaplastic Lymphoma Kinase (ALK) TKI crizotinib, and various cytotoxic agents, using the SRB colorimetric assay in 2D cell culture. We also determined the expression of HER family members, ALK and c-MET in these cancer cell lines using FACS analysis and investigated whether there was any association between the expression level of these growth factor receptors and response to treatment with these agents. Of the 10 ovarian cancer cell lines studied, ES2, SKOV3, CAOV3, COV318 and SW626 were EGFR positive with mean fluorescence intensity (MFI) values of 10, 21, 45, 34 and 11 respectively. Four of the cell lines were also HER-2 positive, with MFI values of 368 (SKOV3), 12 (CAOV3), 13 (A2780) and 16 (A2780CIS) respectively. In contrast, all ovarian tumor cell lines expressed very low levels, or were negative for both HER-3 and HER-4. With the exceptions of COV318 and SW626, which were c-MET and ALK positive, and SKOV3 and CAOV3 cells, which were c-MET positive, all the remaining ovarian cancer cell lines were negative for both ALK and c-MET expression. Of the HER inhibitors, afatinib inhibited the growth of ovarian cancer cell lines with IC50 values ranging from 52nM (CAOV3) to 1.8μM (A2780ADR). Erlotinib also inhibited the growth of these cancer cell lines with IC50 values ranging from 152nM (CAOV3) to 9.6μM (A2780ADR). The growth of ovarian cancer cell lines was also inhibited by crizotinib with IC50 values ranging from 162nM (PA1) to 2.7μM (A2780ADR). Of the three cytotoxic drugs used in this study, paclitaxel was most effective at inhibiting proliferation of ovarian cancer cell lines [IC50 range: 102pM (CaOv3) to 278nM (OVCAR3)], followed by doxorubicin. Interestingly, most ovarian cancer cells were relatively resistant to treatment with cisplatin and had an IC50 above 20μM. We did not find any significant association between the expression levels of individual members of the HER family, co-expression of HER family members, the expression of ALK or c-Met in ovarian cancer cells and response to treatment with the pan-HER inhibitor afatinib, erlotinib, critizinib, and cytotoxic drugs. Our results support the need for further in vitro and in vivo investigations on the therapeutic potential of co-targeting of the HER family of receptors and c-MET and ALK in ovarian cancer cells using a combination of these targeted agents and chemotherapy. Citation Format: Soozana Pivanenthiran, Sharadah Essapen, Alan M. Seddon, Helmout Modjtahedi. Studies on growth response of a panel of human ovarian tumor cell lines to treatment with afatinib, erlotinib, crizotinib and cytotoxic drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4514. doi:10.1158/1538-7445.AM2014-4514