Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839)

Abstract

Gefitinib (Iressa, ZD1839), an inhibitor of epidermal growth factor receptor-tyrosine kinase, has shown potent anti-tumor effects and improved symptoms and quality-of-life of a subset of patients with advanced non-small cell lung cancer (NSCLC). However, a large portion of the patients showed no effect to this agent. To establish a method to predict the response of NSCLC patients to gefitinib, we used a genome-wide cDNA microarray to analyze 33 biopsy samples of advanced NSCLC from patients who had been treated with an identical protocol of second to seventh line gefitinib monotherapy. We identified 51 genes whose expression differed significantly between seven responders and 10 non-responders to the drug. We selected the 12 genes that showed the most significant differences to establish a numerical scoring system (GRS, gefitinib response score), for predicting response to gefitinib treatment. The GRS system clearly separated the two groups without any overlap, and accurately predicted responses to the drug in 16 additional NSCLC cases. The system was further validated by the semi-quantitative RT-PCR, immunohistochemistry and ELISA for serological test. Moreover, we proved that the anti-apoptotic activity of amphiregulin, a protein that was significantly over-expressed in non-responders but undetectable in responders, leads to resistance of NSCLC cells to gefitinib in vitro. Our results suggested that sensitivity of a given NSCLC to gefitinib can be predicted according to expression levels of a defined set of genes that may biologically affect drug sensitivity and survival of lung cancer cells. Our scoring system might eventually lead to achievement of personalized therapy for NSCLC patients.

Effect of an Epidermal Growth Factor Receptor Inhibitor in Mouse Models of Lung Cancer

“…We have also compared the gene expression changes in mouse models exposed to gefitinib with those that have been found to predict sensitivity to gefitinib in human NSCLC (16). As shown in Table 3, we found that gefitinib treatment changed the expression levels for 15 of these 131 genes in mice tumors (fold change, >1.5), which correspond to the expression profiles predicting sensitivity to gefitinib in human NSCLC.…”

“…correspond to the expression profiles predicting sensitivity to gefitinib in human NSCLCs (16). Among them, eight were modulated by gefitinib toward to the normal level (fold change, >1.5).…”

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

“…Using cDNA microarray, increased expression of amphiregulin or TGF-a, known to be the ligands for EGFR, is related with poor response to gefitinib (Kakiuchi et al, 2004). Recently, it was reported that heregulin, ligand for HER3, expression correlates with gefitinib insensitivity (Zhou et al, 2006).…”

RASEF is a Novel Diagnostic Biomarker and a Therapeutic Target for Lung Cancer

“…To identify such molecules, particularly oncoantigens, we had conducted genome-wide expression profile analysis of 120 clinical lung cancer tissue samples, coupled with enrichment of tumor cells by laser microdissection, and then compared the expression profile data with those in 31 normal human tissues (27 adult and 4 fetal organs; refs. [6][7][8][9][10]. To verify the clinicopathologic significance of the respective gene products, we have established a screening system by a combination of the tumortissue microarray analysis of clinical lung cancer materials and RNA interference technique .…”