Abstract A37: Correlation of EGFR ligand expression with response to classical or targeted therapies in non-small cell lung cancer xenografts

Abstract

Abstract Increased levels of the epidermal growth factor receptor (EGFR) and its cognate ligands are common in non-small cell lung cancer (NSCLC) and correlate with a poor prognosis. In the last years targeted therapies against the EGFR were developed, but results of clinical trials were rather disappointing. The identification of biomarkers in NSCLC as predictive factors for an individualized therapy is urgently needed. Twenty six xenografts were established from fresh surgical material from NSCLC patients and characterized with regard to their sensitivity to four cytostatics (Carboplatin, Etoposide, Paclitaxel, Gemcitabine) and two EGFR-inhibitors (Cetuximab, Erlotinib). The expression of EGFR and its ligands epidermal growth factor (EGF), transforming growth factor alpha (TGFα), epiregulin and amphiregulin were examined at mRNA and protein level. Three ligands, which bind exclusively to EGFR (EGF, TGFα and amphiregulin) showed correlations to the mRNA expression of the receptor. Also the mRNA-levels of amphiregulin and epiregulin correlated with each other. The responsiveness towards Etoposide correlated negatively with the EGF-protein (r=-0.479, P<0.05) and with the EGFR-mRNA (r=-0.663, P<0.01) expression. This could mean that the expression of the EGFR-pathway related molecules is able to protect tumor cells from the induction of apoptosis through a cytostatic drug. The response rate to Gemcitabine showed a negative correlation with the TGFα-mRNA level (r=-0.525, P<0.01). Controversially, the amphiregulin-mRNA level correlated positively with the responsiveness to Gemcitabine (r=0.553, P<0.01). A high level of TGFα-mRNA correlated with the resistance to Erlotinib (r=-0.456, P<0.05). The epiregulin-mRNA level showed a positive correlation concerning the sensitivity towards Cetuximab (r=0.476, P<0.05). High EGFR levels seem to be indicative for the resistance to Erlotinib (r=0.636, P<0.05) in squamous cell carcinomas and for the sensitivity to Cetuximab (r=-0.888, P<0.05) in adenocarcinomas. The results of the present study showed the role of the EGFR activated pathways in the dynamics of tumor progression in NSCLC on the one hand and reflect the high level of redundancy and interrelationships of the EGFR signalling pathway on the other hand. The patient-derived NSCLC models are suitable tools for the identification of biomarkers and their regulation mechanisms in a clinically related and standardized way. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A37