Src Inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo.
OBJECTIVE
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.


METHODS
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.
Braman Family Breast Cancer Institute and Division of Biostatistics, Department of Epidemiology and Public Health, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
Fiona
F
Simpkins
Pedro
P
Hevia-Paez
Jun
J
Sun
Wendy
W
Ullmer
Candace A
CA
Gilbert
Thiago
T
da Silva
Ali
A
Pedram
Ellis R
ER
Levin
Isildinha M
IM
Reis
Brian
B
Rabinovich
Diana
D
Azzam
Xiang-Xi
XX
Xu
Tan A
TA
Ince
Ji-Yeon
JY
Yang
Roel G W
RG
Verhaak
Yiling
Y
Lu
Gordon B
GB
Mills
Joyce M
JM
Slingerland
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D052117:Benzodioxoles; D004967:Estrogens; D011799:Quinazolines; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; C515233:saracatinib; D019061:src-Family Kinases