Abstract 1005: Interaction between the estrogen receptor and fibroblast growth factor receptor pathways in non-small cell lung cancer
Authors: Stabile Laura P. , Rothenberger Natalie J. , Farooqui Mariya , Dacic Sanja , Siegfried Jill M. 
Published: July 2017

The estrogen receptor (ER) promotes cell proliferation in non-small cell lung cancer (NSCLC). Since fibroblast growth factors (FGFs) are known regulators of stem cell markers in ER positive breast cancer, we investigated whether a link between the estrogen pathway, FGFs, and stem cell markers could be demonstrated in NSCLC animal models, human cells lines and tumor tissue. In the lungs of female FVB/N mice exposed to the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone, NNK, treatment with the anti-estrogen fulvestrant and/or the aromatase inhibitor anastrozole blocked secretion of both FGF2 and FGF9, and reduced expression of the stem cell markers SOX2 and nanog. These effects were observed in the normal airway epilthelium as well as in both lung preneoplasias and lung adenomas. To investigate the effects of β-estradiol (E2), male mice were administered E2 in the drinking water during exposure to NNK for 4 weeks. In this mouse model, the incidence of carcinogen-induced lung preneoplasias increased 1.8-fold (p&lt;0.05) with E2 exposure accompanied by increased expression of FGF2, FGF9, SOX2, and nanog in airway preneoplasias demonstrating a relationship between activation of the FGF pathway in the lungs, expansion of cells with a stem cell phenotype, and promotion of pre-cancerous changes. In FGFR1 normal copy number NSCLC cell lines that express multiple FGFR family members and secrete several FGFs, E2 treatment caused a significant increase (up to 4-fold; p&lt;0.05) in release of FGF2, an effect that was completely blocked by fulvestrant. Treatment with fulvestrant also resulted in a 30% reduction in phosphorylation of fibroblast growth factor receptor substrate 2, the FGFR docking protein. Upon co-inhibition of ER and FGFRs using fulvestrant and the pan-FGFR inhibitor AZD4547, significantly enhanced (p&lt;0.01) anti-proliferative effects were observed in FGFR1 normal copy number NSCLC cells that show low sensitivity to FGFR inhibitors as single agents. In NSCLC xenografts, the combination of AZD4547 (daily 12.5 mg/kg) and fulvestrant (30 mg/kg twice weekly) resulted in a significantly greater inhibition (67-85% decrease; p&lt;0.05) of tumor growth and decreased expression of Ki67 and stem cell markers compared to each single agent treatment. Furthermore, tumor histology appeared more differentiated and up to a 25% decrease in malignant cellularity was observed with combination treatment compared to each single agent treatment. In NSCLC patient tumors, high ERB expression correlated with high FGFR1 expression (p&lt;0.001). Taken together, these results suggest that interaction between the ER and FGFR pathways in NSCLC promotes a stem-like state. Combining an FGFR inhibitor with an ER pathway inhibitor could be exploited to increase the efficacy of FGFR inhibitors for NSCLC patients who lack FGFR genetic alterations. Supported by P50 CA090440 and the V-Foundation.

Citation Format: Laura P. Stabile, Natalie J. Rothenberger, Mariya Farooqui, Sanja Dacic, Jill M. Siegfried. Interaction between the estrogen receptor and fibroblast growth factor receptor pathways in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1005. doi:10.1158/1538-7445.AM2017-1005