DDB1, which is also involved in NER, is overexpressed in cisplatin resistant cancer cell lines. Elevated glutathione Stransferase P1 expression has been associated with resistance to cisplatin-based chemotherapy in several cancer cell lines. Our gene set comparison analyses demonstrate a significant overlap between the ES cell signatures and our chemotherapy resistance signatures. No prior studies have demonstrated the enrichment of ES cell signatures in clinical samples collected at the time of acquired resistance to cytotoxic chemotherapy. Accumulating evidence suggests an association between a stem cell phenotype and intrinsic chemoresistance. Animal studies have suggested that the cell population exhibiting cancer stem cell characteristics is enriched in xenograft 3,4,5-Trimethoxyphenylacetic acid tumors following chemotherapy. While ES cell signatures may not perfectly reflect the phenotype of gastric cancer stem cells, the enrichment of ES cell signatures in chemoresistant tumors may reflect the survival advantage of tumor cells expressing stem cell regulatory networks. This was validated by our finding that 72 genes shared by the acquired resistance and ES cell signatures were sufficient to predict the initial response to CF. This study has identified a molecular signature for acquired resistance to CF therapy in gastric cancer patients. This signature is able to identify patients likely to have a short or longer term response to CF suggesting it reflects the molecular profile of chemoresistant clones and not non-specific drug effects. Genes contained within this signature, such as Akt/mTOR pathway genes, TRAP1, RAD23A, and GSTP1, may be potentially useful targets for treating tumors resistant to CF therapy. Future studies will be required to confirm these results and to determine whether our novel approach to develop an acquired resistance signature that predicts the therapeutic response of patients to specific chemotherapies is applicable to other types of cancer. A major finding of this study is the identification of a gene signature that emerged in association with tumor resistance to CF therapy in patients who initially benefited from CF therapy. Prior genomic predictors for the chemotherapy response, which were developed using pretreatment tissue samples, have demonstrated a mixed performance. Here we demonstrate that the posttreatment samples collected at the time of acquired resistance, although difficult to obtain clinically, contain unique genomic information that can be used to predict the initial response to cytotoxic chemotherapy. No prior studies have explored acquired resistance using genome-wide analysis of clinical samples, although 2 prior studies evaluated the gene expression pattern in residual disease after the completion of neoadjuvant chemotherapy. Lee, et al. demonstrated that postchemotherapy tumor gene signatures outperforms baseline signatures and clinical predictors in predicting for pathological response and progression-free survival, although these investigators collected posttreatment breast tumors 3 weeks after chemotherapy, not at the time of progressive disease as in our study. Our data is consistent with the aforementioned study that comparing postchemotherapy and prechemotherapy gene expression signatures might be a feasible approach to the identification of predictive signatures. Also, our data provides the first genomic evidence in clinical samples supporting a conventional model for the emergence of acquired resistance whereby resistance emerges through a selective, clonal outgrowth of small 4-(Benzyloxy)phenol populations of pre-existing, chemoresistant tumor cells. While the ”72-gene acquired resistance signature” was developed mainly for potential clinical utility, it contains several overexpressed genes that have been shown to lead to chemoresistance. TRAP1 overexpression leads 
to 5-fluorouracil-, oxaliplatin- and irinotecanresistant phenotypes in different neoplastic cells. Silencing of hHR23A, a nucleotide excision repair enzyme, decreases the nuclear DRP1 level and cisplatin resistance in lung adenocarcinoma cells.