Targeting estrogen receptor signaling with fulvestrant enhances immune and chemotherapy-mediated cytotoxicity of human lung cancer

DH Hamilton, LM Griner, JM Keller, X Hu… - Clinical Cancer …, 2016 - AACR
DH Hamilton, LM Griner, JM Keller, X Hu, N Southall, J Marugan, JM David, M Ferrer
Clinical Cancer Research, 2016AACR
Purpose: The conversion of tumor cells from an epithelial to a mesenchymal-like phenotype,
via a process designated as the epithelial–mesenchymal transition (EMT), is known to
mediate tumor resistance to a variety of cell death inducers, including cytotoxic effector
immune cells. The goal of this study was to identify and potentially repurpose FDA-approved
compounds capable of reducing mesenchymal features of human lung carcinoma cells,
which could be used in combination with immunotherapies or chemotherapeutic strategies …
Abstract
Purpose: The conversion of tumor cells from an epithelial to a mesenchymal-like phenotype, via a process designated as the epithelial–mesenchymal transition (EMT), is known to mediate tumor resistance to a variety of cell death inducers, including cytotoxic effector immune cells. The goal of this study was to identify and potentially repurpose FDA-approved compounds capable of reducing mesenchymal features of human lung carcinoma cells, which could be used in combination with immunotherapies or chemotherapeutic strategies to improve clinical responses.
Experimental Design: In the current report, we have utilized a quantitative high-throughput screening (qHTS) of a pharmaceutical collection of more than 2,000 compounds to identify clinically approved drugs capable of augmenting the sensitivity of mesenchymal-like, lung cancer cells to immune- and chemotherapy-mediated lysis, both in vitro and in vivo.
Results: The estrogen receptor antagonist fulvestrant was shown to reduce mesenchymal features of lung carcinoma cells, resulting in tumor sensitization to the cytotoxic effect of antigen-specific T cells, natural killer (NK) effector cells, and chemotherapy both in vivo and in vitro.
Conclusions: To our knowledge, this is the first report defining a potential role for estrogenic signaling in promoting tumor resistance to immune-mediated cytotoxicity and chemotherapy in lung cancer. Our data demonstrate a robust association between the acquisition of mesenchymal attributes, therapeutic resistance of lung carcinoma cells, and the expression of estrogen receptor 1 (ESR1), supporting further investigations on the role of estrogen signaling in lung cancer progression via the induction of EMT. Clin Cancer Res; 22(24); 6204–16. ©2016 AACR.
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