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Aug 27, 2009

Multigene Signatures Correlate Better to In Vitro Chemosensitivity than Individual Gene Expression

  • Researchers at Queen Alexandra Hospital in the U.K. say that they found a good correlation between genes previously linked to drug sensitivity and resistance with in vitro chemosensitivity when taken together. These findings may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer, they explain.

    “There was considerable heterogeneity between tumors, and while this showed no direct correlation with individual gene expression, there was strong correlation of multigene signatures for many of the single chemotherapy agents and combinations tested,” says Ian Cree, who led the study.

    “The genes identified in this study,” Cree explains, “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.”

    The details are published August 27 in BMC Cancer in a paper called “Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC).”

    The researchers tested docetaxel, cisplatin, gemcitabine, and combinations of the agents on tumor cells taken from 49 fresh NSCLC samples. Chemosensitivity was compared with quantitative expression of putative resistance genes measured by RT-PCR. There were considerable differences between tumors in their sensitivity to individual agents and combinations, though the combination of cisplatin with gemcitabine was usually the most active. 

    When these results were compared to gene expression in the tumors, there was a strong correlation of multigene signatures for many of the single agents and combinations tested. For example, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA-repair enzyme expression. Activity of both drugs was influenced more strongly by the expression of anti- and proapoptotic genes. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene-expression signatures incorporating resistance mechanisms for both agents.

     



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