"Metabolic vulnerabilities for improving therapy response in pancreatic cancer"
Poor response to therapy contributes to a poor clinical outcome in cancer. Pancreatic cancer is especially difficult to treat with therapy. While many studies have focused on tumor cell-extrinsic factors and drug metabolism, how tumors respond to therapy and what intrinsic factors make them respond poorly is not well understood. We investigated tumor cell-intrinsic metabolic alterations that make tumor cells respond poorly. Our studies demonstrate that tumor cell metabolic reprogramming contributes significantly to the tumoral response to therapy. We have identified increased glucose uptake and glycolytic flux correlate with poor responsiveness. We observed that increased nucleotide pools could diminish xenotoxic stress-induced DNA damage in cancer cells. Furthermore, the increased nucleotide levels can directly counter the fluoropyrimidine analogs by a direct molecular competition. These changes are mediated by multiple signaling interactions that result in transcriptional activation of metabolic genes. Overall, these studies demonstrate novel mechanisms of therapy resistance in cancer cells and will lead to improved therapeutic combinations to targeting cancer.
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