The molecular basis of chemosensitivity of non-small cell lung cancer (NSCLC) to cisplatin and docetaxel.

B64

Introduction: NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy. This study has tested the hypothesis that the molecular basis of this difference lies within the known resistance mechanisms inherent to these patients' tumors.Methods: The chemosensitivity of a series of 29 tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA)against cisplatin, and docetaxel, alone and in combination. The results were correlated with quantitative expression of resistance genes measured by RT-PCR in a Taqman Low Density Array (Applied Biosystems) following extraction of mRNA from formalin-fixed paraffin-processed tissue using the AB 6100 extraction system. The results were standardised against the least variable housekeeping gene (PBGD) of those tested. The relationship between chemosensitivity and gene expression was assessed by multiple linear regression analysis.Results: No individual gene expression showed direct correlation with activity in the ATP-TCA. However, docetaxel activity showed some dependence on the expression of Beta-tubulin III, BCRP, MDR1, MRP2 and GSTpi, while cisplatin activity showed some dependence on DNA repair enzyme expression (e.g. ERCC1, MLH1, MSH6). Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel (p < 0.02) and cisplatin (p < 0.001). The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Incorporation of those genes showing best fit into a multiple linear regression model for docetaxel and cisplatin allowed preliminary models to be established for future correlation with clinical outcome.Conclusion: The influence of individual genes on chemosensitivity assessed by the ATP-TCA is limited. However, by multivariate analysis, the expression of genes predicted by previous papers to be involved in resistance do correlate with activity in the ATP-TCA, particularly those related to the apoptotic potential of the tumour as measured by the expression of pro-and anti-apoptotic genes.