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

Fox EM, Miller TW, Balko JM, Kuba MG, Sánchez V, Smith RA, Liu S, González-Angulo AM, Mills GB, Ye F, Shyr Y, Manning HC, Buck E, Arteaga CL
Cancer Res. 2011 71 (21): 6773-84

PMID: 21908557 · PMCID: PMC3206206 · DOI:10.1158/0008-5472.CAN-11-1295

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 (IGF-IR) 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 recurrence-free 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.

©2011 AACR.

MeSH Terms (30)

Adenocarcinoma Animals Antineoplastic Agents, Hormonal Breast Neoplasms Cell Line, Tumor Disease-Free Survival Estradiol Estrogen Receptor Modulators Estrogens Female Fulvestrant Gene Expression Regulation, Neoplastic Humans Imidazoles Insulin Insulin-Like Growth Factor I Mice Mice, Nude Neoplasm Proteins Neoplasms, Hormone-Dependent Protein-Tyrosine Kinases Pyrazines Random Allocation Receptor, IGF Type 1 Receptor, Insulin Receptors, Estrogen RNA Interference Signal Transduction Tamoxifen Xenograft Model Antitumor Assays

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