Abstract
Abstract PURPOSE OF STUDY: Insulin-like growth factor receptor 1 (IGF-1R) signaling has been implicated in the pathogenesis of ovarian cancer. However, IGF-1R inhibitors have had limited efficacy in clinical trials to date. ErbB3, a member of the ErbB receptor tyrosine kinase family, can activate AKT survival signaling through binding of its ligand heregulin (HRG) in a majority of IGF-1 sensitive human cancer cell lines. ErbB3 and pAKT expression are upregulated following IGF-1R blockade and thus activated ErbB3 signaling may represent a potential escape route in the development of resistance to therapy. MM-141, an IGF-1R and ErbB3 directed bispecific antibody, blocks and degrades IGF-1R and ErbB3 containing receptor complexes leading to inhibition of downstream tumor pro-survival signaling to a greater extent as compared to anti-IGF-1R and ErbB3 antibodies. Here we explore the activity of MM-141 in ovarian cancer cell lines in vitro. EXPERIMENTAL PROCEDURES: Growth inhibitory activity of MM-141 was tested on a panel of established ovarian cancer cell lines in vitro. The ability of MM-141 to inhibit basal and IGF-1- and HRG-induced signaling was explored by ELISA and western blotting analyses. DATA SUMMARY: Inhibition of cell proliferation mediated by MM-141 varied among the ovarian cancer cell lines profiled in vitro. Furthermore, MM-141 treatment inhibited basal and ligand-activated IGF-1R, ErbB3 and downstream signaling in a selection of these ovarian cell lines. CONCLUSIONS: Our findings suggest that co-inhibition of IGF-1R and ErbB3 signaling with MM-141 has the potential to be an effective therapy for ovarian cancer patients by blocking redundant survival pathway activation. Citation Format: Michael Curley, Akos Czibere, Alexey Lugovskoy. MM-141, an IGF-1R and ErbB3 directed tetravalent bispecific antibody, inhibits ovarian cancer cell growth in vitro [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1411.
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