Abstract
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Objectives: One mechanism of resistance of HER2-amplified tumors to trastuzumab (Tz) is upregulation of IGF-1 receptors (IGF-1R). We evaluated the clonogenic survival of 4 human BC cell lines after Tz-treatment. Additionally, we evaluated accumulation of 111In-IGF-1-E3R [an analogue of IGF-1 that does not bind IGF-1 binding protein-3 (IGFBP3)] in BC xenografts in athymic mice. Methods: The clonogenic survival of MDA-MB-231 (231), its HER2-transfected (H2N) and Tz-resistant (HR2) subclones was evaluated after treatment with up to 450nM of Tz. The HER2 and IGF-1R density was measured by radioligand binding assay using 111In-Tz and 111In-IGF-1, respectively. Inhibition of binding of 111In-IGF-1 in the presence of a 100-fold excess of IGF-1 or IGFBP3 was studied. Tumor uptake of 111In-IGF-1-ER3 in athymic mice implanted s.c. with 231, H2N, HR2 and HER2-transfected MCF7/HER18 (HER18) cells was studied at 4h post i.v. injection. The effect of co-administration of a 10-fold excess of IGFBP3 on tumor uptake was studied. Results: 231, H2N, HR2 and HER18 cells expressed 1±104, 5±105, 2.5±105 and 1.5±106 HER2 receptors and 8.2±104, 1.4±104, 4±104 and 1±105 IGF-1R/cell, respectively. Clonogenic survival of Tz-treated BC cells was inversely correlated with HER2 density and directly correlated with IGF-1R level with 91±4%, 61±4% and 89±3% of 231, H2N and HR2 cells surviving. Co-treatment of HR2 cells with IGFBP3 decreased their survival to 70±2%. Binding of 111In-IGF-1-ER3 to MCF-7 cells was inhibited 14 and 11-fold by IGF-1 and IGFBP3, respectively. Uptake of 111In-IGF-1-ER3 correlated directly with IGF-1R levels: 2.0±0.5, 1.2±0.3, 0.4±0.1 and 2.5±0.5%ID/g, in 231, H2N, HR2 and HER18 tumors, respectively (r2=0.989). Tumor uptake was not blocked with IGFBP3. 111In-IGF-1-E3R was mainly taken up by the kidneys and the liver (86±13 and 28±4 %ID/g). Conclusions: We conclude that increased IGF-1R expression causes resistance to trastuzumab in BC cells and it may be possible to image this IGF-1R upregulation in vivo using 111In-IGF-1-ER3.
Research Support (if any): This study was supported by grant #03-NOV-0428 from the Ontario Cancer Research Network.
- Society of Nuclear Medicine, Inc.