Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer

Xiaonan Hou, Fei Huang, Luciana F. Macedo, Sean C. Harrington, Karen A. Reeves, Ann Greer, Friedrich Graf Finckenstein, Angela Brodie, Marco M. Gottardis, Joan M. Carboni, Paul Haluska

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7597-7607
Number of pages11
JournalCancer research
Volume71
Issue number24
DOIs
StatePublished - Dec 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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