Abstract
Abstract At present, most non-small cell lung cancer (NSCLC) treatments are not adapted to the individual response of a patient. The stratification of patients for the most efficient response to conventional chemotherapeutics and targeted therapies will improve established therapy schemes and patient's perspectives. Our project aims at unraveling the influence of specific signaling molecules on the response to common NSCLC drugs. We searched for predictive markers for the response of NSCLC tumors to certain drugs and novel combinations of treatments, which may be useful for therapy decisions towards a more efficient personalized treatment. Expression of 77 proteins described to be involved in EGFR signaling (e.g. MAPK, JAK/STAT, PI3K/AKT pathways) and NSCLC disease in general were quantified in 53 patient derived NSCLC xenograft models using the reverse-phase protein array technology (RPPA). The tumor models are characterized by different response rates upon treatment with different chemotherapeutics and EGFR-targeted therapies. The response rates were obtained directly in the xenograft models. After RPPA analysis we associated the protein expression with the response to established chemotherapeutics (e.g. Vinorelbine, Paclitaxel, Carboplatin) and EGFR-targeted therapies (Cetuximab, Erlotinib). Another goal is to analyze the protein expression changes after treatment in dependence on the response rate. Therefore, protein profiles were raised in NSCLC xenograft models before and after treatment with Cetuximab, a chimeric (mouse/human) monoclonal antibody that inhibits EGFR. The major goal in this experimental subset is to find links between the activities of specific proteins and the response to Cetuximab treatment. A similar experiment with Erlotinib (an EGFR inhibitor) treated samples is ongoing. Statistical analysis indicated significant associations between the expression of distinct proteins and the response rate to certain drugs. Proteins of the ErbB signaling pathway were differentially expressed in Carboplatin responders and non-responders. MEK1 upregulation was observed upon Cetuximab treatment in responders. We revealed an association between higher P-SRC expression and increased Gemcitabine response rates. This result fits to observations that describe coherence between SRC inhibition and reduced suppression of cell growth and survival in the presence of Gemcitabine in cancer cell lines. We are now strengthening our results in various validation experiments. First, we selected seven target proteins based on RPPA analysis. Predictive targets for drug sensitivity are being analyzed to investigate the dependency between target protein activity, downstream signaling and response to distinct drugs in tumor cell lines in a pharmacogenomic approach. Therefore, we knocked down target genes in several NSCLC cell lines and unraveled changes in the drug sensitivity. Microarray and protein analyzes were carried out to study the mechanisms of target-drug association by investigating the downstream signaling upon target knockdown. In summary, our study suggests predictive markers for the response of NSCLC tumors to certain drugs, which may be useful for therapy decisions towards a more efficient personalized treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A185.
Published Version
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