title: Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer.
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.
authors: Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Xiaonan
authors: X
authors: Hou
authors: Fei
authors: F
authors: Huang
authors: Luciana F
authors: LF
authors: Macedo
authors: Sean C
authors: SC
authors: Harrington
authors: Karen A
authors: KA
authors: Reeves
authors: Ann
authors: A
authors: Greer
authors: Friedrich Graf
authors: FG
authors: Finckenstein
authors: Angela
authors: A
authors: Brodie
authors: Marco M
authors: MM
authors: Gottardis
authors: Joan M
authors: JM
authors: Carboni
authors: Paul
authors: P
authors: Haluska
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D006801:Humans; D000077289:Letrozole; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011720:Pyrazoles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; C545990:BMS 754807; D004967:Estrogens; D009570:Nitriles; D011720:Pyrazoles; D014227:Triazines; D014230:Triazoles; D013629:Tamoxifen; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol; D000077289:Letrozole; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin