Abstract
Insulin-like growth factor (IGF) signaling has been implicated in the resistance to hormonal therapy in breast cancer. Using a model of postmenopausal, estrogen-dependent breast cancer, we investigated the antitumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor BMS-754807 alone and in combination with letrozole or tamoxifen. BMS-754807 exhibited antiproliferative effects in vitro that synergized strongly in combination with letrozole or 4-hydroxytamoxifen and fulvestrant. Similarly, combined treatment of BMS-754807 with either tamoxifen or letrozole in vivo elicited tumor regressions not achieved by single-agent therapy. Notably, hormonal therapy enhanced the inhibition of IGF-1R/InsR without major side effects in animals. Microarray expression analysis revealed downregulation of cell-cycle control and survival pathways and upregulation of erbB in response to BMS-754807 plus hormonal therapy, particularly tamoxifen. Overall, these results offer a preclinical proof-of-concept for BMS-754807 as an antitumor agent in combination with hormonal therapies in hormone-sensitive breast cancer. Cooperative cell-cycle arrest, decreased proliferation, and enhanced promotion of apoptosis may contribute to antitumor effects to be gauged in future clinical investigations justified by our findings.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Hormonal / administration & dosage
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Antineoplastic Agents, Hormonal / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Synergism
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Estradiol / administration & dosage
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Estradiol / analogs & derivatives
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Estradiol / pharmacology
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Estrogens / metabolism
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Female
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Fulvestrant
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Gene Expression Profiling
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Humans
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Letrozole
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Mammary Neoplasms, Experimental / drug therapy*
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Nitriles / administration & dosage
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Nitriles / pharmacology
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Oligonucleotide Array Sequence Analysis
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Pyrazoles / pharmacology*
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism
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Receptor, Insulin / antagonists & inhibitors
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Receptor, Insulin / genetics
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Receptor, Insulin / metabolism
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Tamoxifen / administration & dosage
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Tamoxifen / analogs & derivatives
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Tamoxifen / pharmacology
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Triazines / pharmacology*
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Triazoles / administration & dosage
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Triazoles / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Hormonal
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BMS 754807
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Estrogens
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Nitriles
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Pyrazoles
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Triazines
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Triazoles
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Tamoxifen
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afimoxifene
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Fulvestrant
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Estradiol
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Letrozole
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Receptor, IGF Type 1
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Receptor, Insulin