JOURNAL ARTICLE

Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects

Laura P Stabile, Jennifer S Lyker, Christopher T Gubish, Weiping Zhang, Jennifer R Grandis, Jill M Siegfried
Cancer Research 2005 February 15, 65 (4): 1459-70
15735034
Identifying new effective therapeutic treatments for lung cancer is critical to improving overall patient survival. We have targeted both the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR) pathways using an ER antagonist, fulvestrant ("Faslodex"), and the selective EGFR tyrosine kinase inhibitor, gefitinib ("Iressa"), in non-small cell lung cancer (NSCLC) cells. Rapid activation of phospho-EGFR and phospho-p44/p42 mitogen-activated protein kinase by estrogen was observed, indicating nonnuclear ER transactivation of EGFR. Additionally, EGFR protein expression was down-regulated in response to estrogen and up-regulated in response to fulvestrant in vitro, suggesting that the EGFR pathway is activated when estrogen is depleted in NSCLC cells. Cell growth and apoptosis were examined in several NSCLC lines that express varying amounts of ERbeta, EGFR, and Neu but no full-length ERalpha. One cell line contained an EGFR mutation. Cells were exposed to 10 nmol/L estrogen and 10 ng/mL EGF and either 1 mumol/L fulvestrant or 1 mumol/L gefitinib alone or in combination. In all cell lines, the drug combination decreased cell proliferation up to 90% and increased apoptosis 2-fold. The relative responses to gefitinib and fulvestrant were similar regardless of ER and EGFR expression and mutation status. In an in vivo lung tumor xenograft model, the drug combination decreased tumor volume in severe combined immunodeficient mice by approximately 60% compared with 49% and 32% for gefitinib and fulvestrant treatment alone, respectively. Antitumor effects of the combination therapy were accompanied by biochemical and histologic evidence of increased apoptosis, decreased phospho-p44/p42 mitogen-activated protein kinase expression, and increased Ki-67 expression compared with individual treatment. These studies provide evidence of a functional interaction between the ER and the EGFR pathways in NSCLC.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
15735034
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"