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

Fiona Simpkins, Pedro Hevia-Paez, Jun Sun, Wendy Ullmer, Candace A. Gilbert, Thiago Da Silva, Ali Pedram, Ellis R. Levin, Isildinha M. Reis, Brian Rabinovich, Diana Azzam, Xiang Xi Xu, Tan A. Ince, Ji Yeon Yang, Roel G.W. Verhaak, Yiling Lu, Gordon Mills, Joyce M. Slingerland

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)5911-5923
Number of pages13
JournalClinical Cancer Research
Volume18
Issue number21
DOIs
StatePublished - Nov 1 2012
Externally publishedYes

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Estrogen Receptors
Ovarian Neoplasms
Estrogens
Cell Cycle
Estrogen Receptor Modulators
saracatinib
In Vitro Techniques
fulvestrant
Heterografts
Gene Expression
Cyclin E
myc Genes
Survival
Poisons
Autophagy
Growth
Cell Cycle Checkpoints
Drug Resistance
Cytoplasm
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Simpkins, F., Hevia-Paez, P., Sun, J., Ullmer, W., Gilbert, C. A., Da Silva, T., ... Slingerland, J. M. (2012). Src inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo. Clinical Cancer Research, 18(21), 5911-5923. https://doi.org/10.1158/1078-0432.CCR-12-1257

Src inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo. / Simpkins, Fiona; Hevia-Paez, Pedro; Sun, Jun; Ullmer, Wendy; Gilbert, Candace A.; Da Silva, Thiago; Pedram, Ali; Levin, Ellis R.; Reis, Isildinha M.; Rabinovich, Brian; Azzam, Diana; Xu, Xiang Xi; Ince, Tan A.; Yang, Ji Yeon; Verhaak, Roel G.W.; Lu, Yiling; Mills, Gordon; Slingerland, Joyce M.

In: Clinical Cancer Research, Vol. 18, No. 21, 01.11.2012, p. 5911-5923.

Research output: Contribution to journalArticle

Simpkins, F, Hevia-Paez, P, Sun, J, Ullmer, W, Gilbert, CA, Da Silva, T, Pedram, A, Levin, ER, Reis, IM, Rabinovich, B, Azzam, D, Xu, XX, Ince, TA, Yang, JY, Verhaak, RGW, Lu, Y, Mills, G & Slingerland, JM 2012, 'Src inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo', Clinical Cancer Research, vol. 18, no. 21, pp. 5911-5923. https://doi.org/10.1158/1078-0432.CCR-12-1257
Simpkins, Fiona ; Hevia-Paez, Pedro ; Sun, Jun ; Ullmer, Wendy ; Gilbert, Candace A. ; Da Silva, Thiago ; Pedram, Ali ; Levin, Ellis R. ; Reis, Isildinha M. ; Rabinovich, Brian ; Azzam, Diana ; Xu, Xiang Xi ; Ince, Tan A. ; Yang, Ji Yeon ; Verhaak, Roel G.W. ; Lu, Yiling ; Mills, Gordon ; Slingerland, Joyce M. / Src inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 21. pp. 5911-5923.
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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

AU - Slingerland, Joyce M.

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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.

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