The dual IGF-1R/InsR inhibitor, BMS-754807, demonstrates synergy in combination with hormonal agents in vitro and enhances in vivo activity in an estrogen-dependent breast cancer model

Insulin like growth factor (IGF) signaling has been implicated in the resistance to hormonal therapy in breast cancer. Combined IGF and estrogen-targeted therapy may improve the benefit of hormonal therapy alone. We employed a postmenopausal model of estrogen-dependent breast cancer in vitro and in vivo using the aromatase-expressing MCF-7/AC-1 cells. Using this model, we investigated the anti-tumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor, BMS754807 alone and in combination with letrozole or tamoxifen in vitro and in vivo. In vitro, the anti-proliferative effects of BMS-754807 in MCF-7/AC-1 cells were profoundly synergistic in combination with letrozole or 4-hydroxytamoxifen, and fulvestrant. Hormonal therapy enhanced the inhibition of IGF-1R/InsR by BMS-754807. After 28 days of treatment, AC-1 xenograft tumors regressed in vivo with the combination of BMS-754807 with either tamoxifen or with letrozole. Tumor regression was significantly improved over single agents BMS-754807, tamoxifen or letrozole at treatment end. Overall, study treatments were tolerable. DNA microarray demonstrated down regulation of cell cycle control and survival pathways and upregulation of erbB in response to BMS-754807 + hormonal therapy, particularly tamoxifen. In conclusion, BMS-754807 demonstrated in vitro and in vivo activity in combination with hormonal therapies in a hormone-sensitive breast cancer model. These data support clinical investigations of the combination. Mechanisms of this synergy may include cooperative cell cycle arrest, decreased proliferation and enhanced promotion of apoptosis. Alternative receptor tyrosine kinase upregulation including EGFR and HER2, may be key resistance mechanisms to combined IGF/estrogen targeting. on April 13, 2017. © 2011 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 31, 2011; DOI: 10.1158/0008-5472.CAN-11-1080