Src inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo
| Autor: | Isildinha M. Reis, Yiling Lu, Ji Yeon Yang, Gordon B. Mills, Ali Pedram, Roel G.W. Verhaak, Xiang Xi Xu, Brian Rabinovich, Joyce M. Slingerland, Wendy Ullmer, Pedro Hevia-Paez, Jun Sun, Candace A. Gilbert, Fiona Simpkins, Tan A. Ince, Thiago G. da Silva, Diana J. Azzam, Ellis R. Levin |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
medicine.medical_specialty medicine.drug_class Estrogen receptor Antineoplastic Agents Apoptosis Biology Article Mice Internal medicine Cell Line Tumor medicine Animals Humans Benzodioxoles Fulvestrant Cell Proliferation Cell Nucleus Ovarian Neoplasms Estradiol Cell growth Cancer Estrogens Cell cycle medicine.disease Xenograft Model Antitumor Assays Enzyme Activation Gene Expression Regulation Neoplastic Disease Models Animal Protein Transport Endocrinology src-Family Kinases Oncology Receptors Estrogen Estrogen Drug Resistance Neoplasm Gene Knockdown Techniques Cancer research Quinazolines Female Ovarian cancer Proto-oncogene tyrosine-protein kinase Src medicine.drug Protein Binding |
| Popis: | Purpose: More effective, less toxic treatments for recurrent ovarian cancer are needed. Although more than 60% of ovarian cancers express the estrogen receptor (ER), ER-targeted drugs have been disappointing due to drug resistance. In other estrogen-sensitive cancers, estrogen activates Src to phosphorylate p27 promoting its degradation and increasing cell-cycle progression. Because Src is activated in most ovarian cancers, we investigated whether combined Src and ER blockade by saracatinib and fulvestrant would circumvent antiestrogen resistance. Experimental Design: ER and Src were assayed in 338 primary ovarian cancers. Dual ER and Src blockade effects on cell cycle, ER target gene expression, and survival were assayed in ERα+ ovarian cancer lines, a primary human ovarian cancer culture in vitro, and on xenograft growth. Results: Most primary ovarian cancers express ER. Src activity was greater in ovarian cancer lines than normal epithelial lines. Estrogen activated Src, ER-Src binding, and ER translocation from cytoplasm to nucleus. Estrogen-mediated mitogenesis was via ERα, not ERβ. While each alone had little effect, combined saracatinib and fulvestrant increased p27 and inhibited cyclin E-Cdk2 and cell-cycle progression. Saracatinib also impaired induction of ER-target genes c-Myc and FOSL1; this was greatest with dual therapy. Combined therapy induced autophagy and more effectively inhibited ovarian cancer xenograft growth than monotherapy. Conclusions: Saracatinib augments effects of fulvestrant by opposing estrogen-mediated Src activation and target gene expression, increasing cell-cycle arrest, and impairing survival, all of which would oppose antiestrogen resistance in these ER+ ovarian cancer models. These data support further preclinical and clinical evaluation of combined fulvestrant and saracatinib in ovarian cancer. Clin Cancer Res; 18(21); 5911–23. ©2012 AACR. |
| Databáze: | OpenAIRE |
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