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]