RT Journal Article SR Electronic T1 HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924 JF Molecular Cancer Therapeutics JO Mol Cancer Ther FD American Association for Cancer Research SP 2589 OP 2598 DO 10.1158/1535-7163.MCT-08-0493 VO 7 IS 9 A1 Haluska, Paul A1 Carboni, Joan M. A1 TenEyck, Cynthia A1 Attar, Ricardo M. A1 Hou, Xiaonan A1 Yu, Chunrong A1 Sagar, Malvika A1 Wong, Tai W. A1 Gottardis, Marco M. A1 Erlichman, Charles YR 2008 UL http://mct.aacrjournals.org/content/7/9/2589.abstract AB We have reported previously the activity of the insulin-like growth factor-I (IGF-IR)/insulin receptor (InsR) inhibitor, BMS-554417, in breast and ovarian cancer cell lines. Further studies indicated treatment of OV202 ovarian cancer cells with BMS-554417 increased phosphorylation of HER-2. In addition, treatment with the pan-HER inhibitor, BMS-599626, resulted in increased phosphorylation of IGF-IR, suggesting a reciprocal cross-talk mechanism. In a panel of five ovarian cancer cell lines, simultaneous treatment with the IGF-IR/InsR inhibitor, BMS-536924 and BMS-599626, resulted in a synergistic antiproliferative effect. Furthermore, combination therapy decreased AKT and extracellular signal-regulated kinase activation and increased biochemical and nuclear morphologic changes consistent with apoptosis compared with either agent alone. In response to treatment with BMS-536924, increased expression and activation of various members of the HER family of receptors were seen in all five ovarian cancer cell lines, suggesting that inhibition of IGF-IR/InsR results in adaptive up-regulation of the HER pathway. Using MCF-7 breast cancer cell variants that overexpressed HER-1 or HER-2, we then tested the hypothesis that HER receptor expression is sufficient to confer resistance to IGF-IR-targeted therapy. In the presence of activating ligands epidermal growth factor or heregulin, respectively, MCF-7 cells expressing HER-1 or HER-2 were resistant to BMS-536924 as determined in a proliferation and clonogenic assay. These data suggested that simultaneous treatment with inhibitors of the IGF-I and HER family of receptors may be an effective strategy for clinical investigations of IGF-IR inhibitors in breast and ovarian cancer and that targeting HER-1 and HER-2 may overcome clinical resistance to IGF-IR inhibitors. [Mol Cancer Ther 2008;7(9):2589–98]