Src inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo
Clinical Cancer Research, 08/21/2012
Simpkins FA et al. – 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 anti-estrogen resistance in these ER+ OVCA models. These data support further pre-clinical and clinical evaluation of combined fulvestrant and saracatinib in OVCA.Methods
- ER and Src were assayed in 338 primary OVCAs.
- Dual ER and Src blockade effects on cell cycle, ER target gene expression, and survival were assayed in ER alpha + OVCA lines, a primary human OVCA culture in vitro, and on xenograft growth.
- Most primary OVCAs express ER. Src activity was greater in OVCA lines than normal epithelial lines. Estrogen activated Src, ER-Src binding and ER translocation from cytoplasm to nucleus.
- Estrogen mediated mitogenesis was via ER alpha, not ER beta While each alone had little effect, combined saracatinib and fulvestrant increased p27, inhibited cyclin E-Cdk2 and cell cycle progression.
- Saracatinib also impaired induction of ER-target genes Myc and FOSL1; this was greatest with dual therapy.
- Combined therapy induced autophagy and more effectively inhibited OVCA xenograft growth than monotherapy.