Abstract 630: Responses of human pancreatic cancer cells to treatment with insulin-like growth factor receptor (IGF-IR) tyrosine kinase inhibitor NVP-AEW541 alone and in combination with anti-EGFR mAb ICR62 or cytotoxic drugs

Abstract

Abstract Aberrant expression and activation of growth factor receptor signalling pathways including epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGF-IR) have been reported in a wide range of epithelial cancers and have been associated with increased cell proliferation, reduced apoptosis, invasion and metastasis. Of the growth factor receptor inhibitors, the EGFR inhibitor erlotinib has been approved for the treatment of pancreatic cancer. However, its overall therapeutic efficacy can be of short duration. In some studies, signalling with the IGF-IR has been associated with resistance to therapy with the EGFR inhibitors. In this study, using the Sulforhodamine B colorimetric assay, we investigated the sensitivity of a panel of human pancreatic cancer cell lines (PT-45, AsPC1, PANC1, MiaPaca2, BxPC3, Capan1 and FA6) to treatment with IGF-IR tyrosine kinase inhibitor NVP-AEW541 alone or in combination with anti-EGFR monoclonal antibody (mAb) ICR62 and cytotoxic agents (i.e. 5-FU, doxycycline and gemcitabine). We also investigated the association between the expression levels of IGF-IR and EGFR in these tumour cells, determined by flow cytometry, and their responses to treatment with NVP-AEW541 and/or ICR62. At concentrations above 5μM, NVP-AEW541 inhibited completely the growth of most of the pancreatic cancer cell lines with IC50 values ranging from 342nM (FA6) to 2.73μM (PT45). At maximum concentration of 150nM used in this study, ICR62 did not have any effect on the growth of human pancreatic tumour cell lines. In addition, treatment with a combination of ICR62 and NVP-AEW541 did not enhance the inhibitory effect of the single agent in pancreatic cancer cells. Interestingly, treatment with a combination of NVP-AEW541 and gemcitabine was found to be synergistic for AsPC1 and PANC1 cells, additive for BxPC3, MiaPaca2 and PT-45 cells, but antagonistic for FA6 and CAPAN1 cells. We also examined the cell cycle distribution of BxPC3 cells following treatment with NVP-AEW541 and found an increase in the population of cells in sub-G1 and G0/G1 phases. In contrast, gemcitabine treatment of BxPC3 cells was accompanied by an increase in the populations of cells in both the sub-G1 and S phases of the cell cycle. Taken together, our results suggest that dual targeting of the EGFR and IGF-IR in pancreatic cancer cells by a combination of ICR62 and NVP-AEW541 is not superior to treatment with the single agent in vitro. Further investigations in vivo on the anti-tumour activity of the NVP-AEW541 in combination with ICR62 and cytotoxic drugs in pancreatic cancer are warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 630. doi:10.1158/1538-7445.AM2011-630