A retinoid X receptor (RXR)-selective agonist bexarotene produces synergistic growth inhibitory activity with gefitinib in non-small-cell lung cancer (NSCLC) cell lines

Abstract

7157 Background: Gefitinib (Iressa) is an orally active epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Bexarotene (Targretin) is a selective RXR agonist approved for the treatment of CTCL, and with clinical activity enhancing survival and delaying progression in NSCLC patients. Our previously published data (Cancer Res. 2001) has shown that bexarotene can suppress the growth of epithelial tumors by modulating the expression and function of EGFR and its ligand, TGFα. Methods: The expression of EGFR, Her-2, EGF, and TGFα were evaluated in a panel of 10 NSCLC cell lines, representing different histomorphologies. Cells were treated with bexarotene either alone or in combination with Iressa and growth and viability were examined. Combination treatments were either concomitant or sequential. Results: Exposure of NSCLC cell lines to bexarotene as a single agent had modest growth inhibitory effects (at > 1 μM). However, exposure of several NSCLC lines to bexarotene (1–3 μM) produced significant decreases in the expression of EGFR, Her-2 and TGFα mRNA and protein. EGF levels were also decreased to a much lesser degree. Bexarotene combined with Iressa produced an enhanced growth inhibitory activity (a left-ward shift of 3–5 fold in the IC50) when compared to Iressa alone. Analysis of the growth inhibition of the bexarotene /gefitinib combination demonstrated a synergistic (CI<1) concentration-dependent growth inhibition in several of the NSCLC cell lines. The extent of synergy between bexarotene and gefitinib was greater at modest drug effect (≤IC50). Conclusions: These results suggest that bexarotene can inhibit the expression of several components of the EGFR-Her-2 signaling pathways, and can cooperate with EGFR-targeted agents to decrease proliferation of NSCLC cells in vitro. These data support the clinical observation, also presented at this meeting (Dragnev, K. et al) suggesting that Targretin has beneficial effects when used with EGFR-TKIs in advanced NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ligand Pharmaceuticals Ligand Pharmaceuticals