PMID- 18765823 OWN - NLM STAT- MEDLINE DCOM- 20081022 LR - 20211020 IS - 1535-7163 (Print) IS - 1538-8514 (Electronic) IS - 1535-7163 (Linking) VI - 7 IP - 9 DP - 2008 Sep TI - HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924. PG - 2589-98 LID - 10.1158/1535-7163.MCT-08-0493 [doi] 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. FAU - Haluska, Paul AU - Haluska P AD - Department of Oncology, Mayo Clinic, 200 First Street, South West, Rochester, MN 55905, USA. haluska.paul@mayo.edu FAU - Carboni, Joan M AU - Carboni JM FAU - TenEyck, Cynthia AU - TenEyck C FAU - Attar, Ricardo M AU - Attar RM FAU - Hou, Xiaonan AU - Hou X FAU - Yu, Chunrong AU - Yu C FAU - Sagar, Malvika AU - Sagar M FAU - Wong, Tai W AU - Wong TW FAU - Gottardis, Marco M AU - Gottardis MM FAU - Erlichman, Charles AU - Erlichman C LA - eng GR - L30 CA103784/CA/NCI NIH HHS/United States GR - K12 CA090628/CA/NCI NIH HHS/United States GR - P50 CA116201/CA/NCI NIH HHS/United States GR - P30 CA015083/CA/NCI NIH HHS/United States GR - L30 CA103784-02/CA/NCI NIH HHS/United States GR - CA116201-01/CA/NCI NIH HHS/United States GR - CA090628-05/CA/NCI NIH HHS/United States GR - N01 CA015083/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20080902 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (Antineoplastic Agents) RN - 0 (BMS 536924) RN - 0 (Benzimidazoles) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridones) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.10.1 (Receptor, Insulin) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Antineoplastic Agents/pharmacology MH - Benzimidazoles/*pharmacology MH - Cell Death/drug effects MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Drug Resistance, Neoplasm/*drug effects MH - Drug Screening Assays, Antitumor MH - Drug Synergism MH - Enzyme Activation/drug effects MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Female MH - Humans MH - Ovarian Neoplasms/enzymology/pathology MH - Phosphorylation/drug effects MH - Protein Kinase Inhibitors/pharmacology MH - Proto-Oncogene Proteins c-akt/metabolism MH - Pyridones/*pharmacology MH - Receptor Cross-Talk/drug effects MH - Receptor, ErbB-2/antagonists & inhibitors/*metabolism MH - Receptor, IGF Type 1/*antagonists & inhibitors MH - Receptor, Insulin/antagonists & inhibitors MH - Signal Transduction/*drug effects PMC - PMC2614316 MID - NIHMS68744 EDAT- 2008/09/04 09:00 MHDA- 2008/10/23 09:00 PMCR- 2009/09/01 CRDT- 2008/09/04 09:00 PHST- 2008/09/04 09:00 [pubmed] PHST- 2008/10/23 09:00 [medline] PHST- 2008/09/04 09:00 [entrez] PHST- 2009/09/01 00:00 [pmc-release] AID - 1535-7163.MCT-08-0493 [pii] AID - 10.1158/1535-7163.MCT-08-0493 [doi] PST - ppublish SO - Mol Cancer Ther. 2008 Sep;7(9):2589-98. doi: 10.1158/1535-7163.MCT-08-0493. Epub 2008 Sep 2.