A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer

Emily M. Fox, Todd W. Miller, Justin M. Balko, Maria G. Kuba, Violeta Sánchez, R. Adam Smith, Shuying Liu, Ana María González-Angulo, Gordon B. Mills, Fei Ye, Yu Shyr, H. Charles Manning, Elizabeth Buck, Carlos L. Arteaga

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    109 Scopus citations

    Abstract

    Estrogen receptor α (ER)-positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER + breast cancer cells resistant to long-term estrogen deprivation (LTED). A kinome-wide siRNA screen showed that the insulin receptor (InsR) is required for growth of MCF-7/LTED cells. Knockdown of InsR and/or insulin-like growth factor-I receptor (IGFIR) inhibited growth of 3 of 4 LTED cell lines. Inhibition of InsR and IGF-IR with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone-independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K/AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-IR monoclonal antibody MAB391 was ineffective. Combined treatment with OSI-906 and the ER downregulator fulvestrant more effectively suppressed hormone-independent tumor growth than either drug alone. Finally, an insulin/IGF-I gene expression signature predicted recurrencefree survival in patients with ER + breast cancer treated with the antiestrogen tamoxifen. We conclude that therapeutic targeting of both InsR and IGF-IR should be more effective than targeting IGF-IR alone in abrogating resistance to endocrine therapy in breast cancer.

    Original languageEnglish (US)
    Pages (from-to)6773-6784
    Number of pages12
    JournalCancer Research
    Volume71
    Issue number21
    DOIs
    StatePublished - Nov 1 2011

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    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Fox, E. M., Miller, T. W., Balko, J. M., Kuba, M. G., Sánchez, V., Smith, R. A., Liu, S., González-Angulo, A. M., Mills, G. B., Ye, F., Shyr, Y., Manning, H. C., Buck, E., & Arteaga, C. L. (2011). A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Research, 71(21), 6773-6784. https://doi.org/10.1158/0008-5472.CAN-11-1295