Abstract
It was the aim of our study to establish an extensive panel of non-small cell lung cancer (NSCLC) xenograft models useful for the testing of novel compounds and for the identification of biomarkers. Starting from 102 surgical NSCLC specimens, which were obtained from primarily diagnosed patients with early-stage tumors (T(2)/T(3)), 25 transplantable xenografts were established and used for further investigations. Early passages of the NSCLC xenografts revealed a high degree of similarity with the original clinical tumor sample with regard to histology, immunohistochemistry, as well as mutation status. The chemotherapeutic responsiveness of the xenografts resembled the clinical situation in NSCLC with tumor shrinkage obtained with paclitaxel (4 of 25), gemcitabine (3 of 25), and carboplatin (3 of 25) and lower effectiveness of etoposide (1 of 25) and vinorelbine (0 of 11). Twelve of 25 NSCLC xenografts were >50% growth inhibited by the anti-epidermal growth factor receptor (EGFR) antibody cetuximab and 6 of 25 by the EGFR tyrosine kinase inhibitor erlotinib. The response to the anti-EGFR therapies did not correlate with mutations in the EGFR or p53, but there was a correlation of K-ras mutations and erlotinib resistance. Protein analysis revealed a heterogeneous pattern of expression. After treatment with cetuximab, we observed a down-regulation of EGFR in 2 of 6 sensitive xenograft models investigated but never in resistant models. An extensive panel of patient-derived NSCLC xenografts has been established. It provides appropriate models for testing marketed as well as novel drug candidates. Additional expression studies allow the identification of stratification biomarkers for targeted therapies.
Highlights
It was the aim of our study to establish an extensive panel of non-small cell lung cancer (NSCLC) xenograft models useful for the testing of novel compounds and for the identification of biomarkers
Clinical trials in non-small cell lung cancer (NSCLC) patients with therapies targeting the epidermal growth factor receptor (EGFR) have been accompanied with great expectations but have far shown only limited achievement compared with chemotherapy (1 – 5)
There are several reports suggesting that the phosphoinositide 3-kinase/AKT signaling pathway is central to NSCLC growth and survival [16]
Summary
It was the aim of our study to establish an extensive panel of non-small cell lung cancer (NSCLC) xenograft models useful for the testing of novel compounds and for the identification of biomarkers. The establishment of patient-derived xenografts is described These models show a high concordance with the clinical samples concerning histology and gene and protein expression. Concerning the intended identification of biomarkers for EGFR-targeted therapies, our results reveal a lack of correlation to EGFR and p53 mutations but confirm the relative importance of K-ras mutations for the resistance phenotype These data can directly support clinical decisions concerning the stratification of patients with NSCLC to be treated with cetuximab or erlotinib. Comprehensive searches for predictive biomarkers trying to define genes or proteins with therapeutic relevance are currently pursued These studies use mainly clinical samples [18, 19], cell lines [20, 21], or cell-line derived xenograft models (20, 22 – 25).
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