SAN ANTONIO—Fibroblast growth factor receptor 1 (FGFR1) gene and ligand co-amplification is associated with endocrine resistance in estrogen receptor-positive (ER+) breast cancer cells, according to a preclinical in vitro study presented at the 2015 San Antonio Breast Cancer Symposium.1
“FGF3/4/19 and FGFR1 expression are upregulated upon estrogen deprivation, suggesting it is a mechanism of adaptation and/or resistance to endocrine therapy,” reported lead author Luigi Formisano, of Vanderbilt University Medical Center in Nashville, TN. “We hypothesize ER+/FGFR1-amplified tumors should be treated with a combination of antiestrogens and FGFR antagonists.”
FGFR1 interaction with ER in the nucleus “increases upon estrogen deprivation in FGFR1-amplified primary tumors,” he said. “FGFR1 tyrosine kinase activity is required for the interaction of FGFR1 and estrogen receptor. The FGFR1 TKI lucitanib reduces ER transcriptional activity.”
ER+ breast cancers initially respond to antiestrogens but eventually become hormone-independent and recur, Formisano noted. FGFR1 is amplified in approximately 10% of ER+ breast cancers (and up to 27% of luminal B-subtype breast cancers) and amplification is associated with resistance to antiestrogen therapy and poor outcomes among patients with ER+ breast cancer, he noted. It has been hypothesized that FGFR signaling mediates resistance to hormonal therapies through activation of the MAPK and PI3K pathways.
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The research team is now investigating genes modulated by ER/FGFR1 in ER+ breast and preclinical “in-vivo antitumor efficacy of dual inhibition of FGFR1 and ER in ER+/FGFR1-amplified patient-derived breast cancer xenografts.”
- Formisano L, Young CD, Bhola NE, et al. Nuclear FGFR1 interaction with estrogen receptor (ER) α is associated with resistance to endocrine therapy in ER+/FGFR1-amplified breast cancer. Oral presentation at: San Antonio Breast Cancer Symposium 2015; December 10, 2015; San Antonio, TX.