title: A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer.
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 (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.
authors: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.
authors: Emily M
authors: EM
authors: Fox
authors: Todd W
authors: TW
authors: Miller
authors: Justin M
authors: JM
authors: Balko
authors: Maria G
authors: MG
authors: Kuba
authors: Violeta
authors: V
authors: Sánchez
authors: R Adam
authors: RA
authors: Smith
authors: Shuying
authors: S
authors: Liu
authors: Ana María
authors: AM
authors: González-Angulo
authors: Gordon B
authors: GB
authors: Mills
authors: Fei
authors: F
authors: Ye
authors: Yu
authors: Y
authors: Shyr
authors: H Charles
authors: HC
authors: Manning
authors: Elizabeth
authors: E
authors: Buck
authors: Carlos L
authors: CL
authors: Arteaga
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor / Q000187:drug effects; D018572:Disease-Free Survival; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use; D004967:Estrogens; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000503:physiopathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011719:Pyrazines / Q000627:therapeutic use; D034622:RNA Interference; D011897:Random Allocation; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000502:physiology*; D011960:Receptors, Estrogen / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D007093:Imidazoles; D007328:Insulin; D009363:Neoplasm Proteins; D011719:Pyrazines; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin