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

Research output: Contribution to journalArticlepeer-review

116 Citations (Scopus)

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
Pages (from-to)6773-6784
Number of pages12
JournalCancer Research
Volume71
Issue number21
DOIs
Publication statusPublished - 2011 Nov 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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