Abstract 616: R1507, the human monoclonal antibody targeting the insulin-like growth factor receptor (IGF-1R), in combination with cetuximab, can reverse acquired resistance to cetuximab in pancreatic and colon cancer models

Abstract

Abstract Background: Cetuximab, the chimeric monoclonal antibody (mAb) directed against the human epidermal growth factor receptor (EGFR) is widely used for the treatment of colorectal cancer and is also effective in pancreatic cancer preclinical models. Acquired resistance to cetuximab is common and the IGF-1R signaling pathway is critically involved in this process. We hypothesized that the combined activation of EGFR and IGF1-R is responsible for the constitutive activation of the transcriptional factor STAT-3 which in turn results in acquired resistance to cetuximab in colorectal and pancreatic tumors. Targeting this activation of EGFR and IGF1-R using the combination of cetuximab and R1507 could potentially reverse this resistance. Methods: A model of pancreatic cancer (PC) cell line resistant in vivo to cetuximab was established by injecting orthotopically, luciferase- and GFP- expressing AsPC-1 human PC cells into nude mice. Once established these tumors in vivo, the mice were treated with cetuximab 500 µg ip bi-weekly until the 34th week, when tumor growth occurred despite cetuximab due to acquired resistance. The tumors were rapidly excised and the GFP- positive cells were selected to establish the cetuximab- resistant clone AsPC-1-CR. Two models of colon cancer (CRC) cell line with acquired resistance in vivo to cetuximab, SW480-CR and GEO-CR, were established as previously described (Bianco et al. Clin Cancer Res. 2008 14(16):5069-80). MTT assay was used to assess the antitumor activity of cetuximab, R1507, and the combination in vitro. Synergy was assessed according the combination-index method of Chou and Talalay. The expression of IGF1-R was studied by Western blot. STAT-3 activation was analyzed by EMSA. Inhibition of directional cell migration was studied in an in vitro wound-healing model. Results: The cetuximab- resistant PC and CRC cell lines, showed a significantly lower in vitro sensitivity to cetuximab when compared to the respective control cell lines. AsPC-1-CR and SW480-CR cells demonstrated a higher expression of IGF1-R. STAT-3 DNA binding activity was significantly increased in all of the cetuximab- resistant cells as compared with control cell lines. The addition of R1507 did not improve the antitumor activity of cetuximab in the control cell lines. However, the combination of cetuximab + R1507 reversed the resistance to cetuximab in the AsPC-1-CR and SW480-CR cell lines, thereby demonstrating synergistic antitumor activity in the setting of acquired resistance. R1507+cetuximab also significantly inhibited the migration of cetuximab- resistant CRC cells. Conclusion: IGF-1R inhibition using R1507 is a promising approach to restore the sensitivity to cetuximab in PC and CRC cells that have developed acquired resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 616.