title: HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924.
abstract: 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.
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First Street, South West, Rochester, MN 55905, USA. haluska.paul@mayo.edu
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Cynthia
authors.initials: C
authors.lastname: TenEyck
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Attar
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Hou
authors.forename: Chunrong
authors.initials: C
authors.lastname: Yu
authors.forename: Malvika
authors.initials: M
authors.lastname: Sagar
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman