TY - JOUR
T1 - Src inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo
AU - Simpkins, Fiona
AU - Hevia-Paez, Pedro
AU - Sun, Jun
AU - Ullmer, Wendy
AU - Gilbert, Candace A.
AU - Da Silva, Thiago
AU - Pedram, Ali
AU - Levin, Ellis R.
AU - Reis, Isildinha M.
AU - Rabinovich, Brian
AU - Azzam, Diana
AU - Xu, Xiang Xi
AU - Ince, Tan A.
AU - Yang, Ji Yeon
AU - Verhaak, Roel G.W.
AU - Lu, Yiling
AU - Mills, Gordon B.
AU - Slingerland, Joyce M.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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 cancermodels. These data support further preclinical and clinical evaluation of combined fulvestrant and saracatinib in ovarian cancer.
AB - 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 cancermodels. These data support further preclinical and clinical evaluation of combined fulvestrant and saracatinib in ovarian cancer.
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U2 - 10.1158/1078-0432.CCR-12-1257
DO - 10.1158/1078-0432.CCR-12-1257
M3 - Article
C2 - 22896656
AN - SCOPUS:84868587857
SN - 1078-0432
VL - 18
SP - 5911
EP - 5923
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -