Strategies to Target Estrogen-Related Tumor Promoting Mechanisms in Lung Cancer

[摘要] Despite clinical advancements with targeted and immune therapies, lung cancer remains the leading cause of cancer related deaths in the United States. Scant improvements in the five-year survival rate over the past decade necessitate the development of more efficacious therapeutic approaches. Epidemiological reports and preclinical studies have demonstrated involvement of the estrogen pathway, mediated through estrogen receptor β-1 (ERβ), in the development and promotion of lung tumorigenesis. Strategies for targeting the estrogen pathway include anti-estrogens and aromatase inhibitors (AIs), either as single agents or combined with other therapies. The primary objective of this study was to identify and target interactions between the estrogen signaling pathway and the fibroblast growth factor (FGF) pathway and identify additional estrogen-related tumor promoting mechanisms in non-small cell lung cancer (NSCLC). Fibroblast growth factor receptor 1 (FGFR1) was significantly over-expressed in ERβ high tumors, while the decoy receptor, fibroblast growth factor receptor like-1 (FGFR5), was down-regulated. NSCLC cell lines lacking FGFR1 amplification expressed multiple FGFRs and secreted several FGFs. β-estradiol (E2) treatment significantly enhanced FGF2 release, an effect blocked by the anti-estrogen fulvestrant. Furthermore, co-targeting the E2 and FGF pathways with fulvestrant and the pan-FGFR inhibitor AZD4547 resulted in greater anti-tumor effects both in vitro and in vivo compared to single pathway inhibition. These results demonstrate crosstalk between the two pathways in NSCLC, and suggest clinical utility of a pan-FGFR inhibitor in combination with an anti-estrogen in a subset of NSCLC patients. Previous reports of aromatase expression in pulmonary tumor macrophages, and up-regulation of anti-oxidant signaling with AIs, indicate a potential interaction between estrogen signaling and inflammation in lung cancer.Utilizing an in vivo NSCLC xenograft model, the AIs exemestane and letrozole significantly inhibited tumor proliferation, reduced Ki67 expression, altered tumor histology, and increased anti-inflammatory signaling. Finally, we demonstrated fulvestrant enhanced therapeutic sensitivity and inhibited the migration of NSCLC cells resistant to the heat shock protein 90 (HSP90) inhibitor ganetespib, but not through a reversal of epithelial-mesenchymal transition. Together, the results of this study highlight the pervasive role of estrogen signaling in lung cancer and provide rationale for combinatorial strategies involving hormonal agents for lung cancer treatment.

[发布机构] the University of Pittsburgh