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Researchers Develop Assay for Predicting Lung Cancer Drug Response

NEW YORK (GenomeWeb News) – In a paper appearing online today in the journal BMC Cancer, a British-led team of scientists showed that looking at the expression of a set of known or suspected drug response genes may offer clues for choosing the most promising non-small cell lung cancer treatments.

The researchers used an ATP-based tumor chemosensitivity assay to assess the expression of more than 90 genes in dozens of NSCLC tumor samples exposed to as many as six drug treatments. They found that expression changes in the drug resistance and transport genes corresponded to the tumor chemosensitivity patterns observed in the lab — raising the possibility that such expression signatures could prove useful for guiding lung cancer therapy.

"There was considerable heterogeneity between tumors, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single chemotherapy agents and combinations tested," senior author Ian Cree, a researcher with Queen Alexandra Hospital's Translational Oncology Research Centre in the UK, said in a statement. "This may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer."

Cree is also director of the translational research company CanTech, which funded the study along with Sanofi-Aventis and Applied Biosystems.

Chemotherapy has variable results for those with NSCLC. For instance, the researchers explained, decreased effectiveness for treatments involving cisplatin in combination with other drugs has been attributed to processes such as muted drug accumulation, enhanced drug detoxification, or improved tumor DNA repair.

"Not all NSCLC patients will benefit from the same treatment, and the molecular mechanisms involved are still largely unknown," the authors wrote. "This study has tested the hypothesis that the molecular basis of this difference lies within the known resistance mechanisms inherent to these patients' tumors."

To determine whether expression signatures for known drug response or resistance genes could be informative for predicting treatment effectiveness, Cree and his colleagues used the ATP-TCA drug sensitivity testing approach in combination with expression studies.

The team screened 49 formalin-fixed paraffin-embedded NSCLC tumor tissues with three chemotherapy drugs — docetaxel, cisplatin, gemcitabin — either alone or in pairs. For the same tumors, they also evaluated expression patterns for 92 genes previously implicated in various aspects of drug resistance using CanTech's Chemosensitivity Gene Expression Array.

The array, developed using the Taqman Array microfluidic qRT-PCR card, also evaluates four housekeeping genes in order to standardize results from one tumor to the next.

As expected, the researchers found varying degrees of sensitivity to the drug treatments tested in the tumor tissues. But when they integrated their tumor drug response and CGEA gene expression data, the team found characteristic expression changes in the resistance-related genes that correlated with the various drugs and their effect on the tumor tissue.

The affected genes came from pathways involved in everything from metabolism and cellular drug pumps to DNA repair and apoptosis. For instance, the team's results linked a combination cisplatin-gemcitabine treatment effect with 22 genes. Among them: genes coding for drug pumps as well as others involved in apoptosis or DNA repair.

"The genes identified in this study fall into several categories, linked with much studied mechanisms such as metabolism within the cell, membrane drug pumps, and DNA repair, but also with apoptosis, suggesting that the general susceptibility of the cell to undergo this process may be an important determinant of tumor chemosensitivity, outweighing more specific mechanisms," Cree said in a statement.

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