Insights into Gemcitabine Resistance and the Potential for Therapeutic Monitoring

Introduction—Gemcitabine is an important component of pancreatic cancer clinical management. Unfortunately, acquired gemcitabine resistance is widespread and there are limitations to predicting and monitoring therapeutic outcomes. Objective—To investigate the potential of metabolomics to differentiate pancreatic cancer cells that develops resistance or respond to gemcitabine treatment. Results—We applied 1D 1H and 2D 1H-13C HSQC NMR methods to profile the metabolic signature of pancreatic cancer cells. 13C6-glucose labeling identified thirty key metabolites uniquely altered between wild-type and gemcitabine-resistant cells upon gemcitabine treatment. Gemcitabine resistance was observed to reprogram glucose metabolism and to enhance the pyrimidine synthesis pathway. Myo-inositol, taurine, glycerophosphocholine and creatinine phosphate exhibited a “binary switch” in response to gemcitabine treatment and acquired resistance. Conclusion—Metabolic differences between naïve and resistant pancreatic cancer cells and, accordingly, their unique responses to gemcitabine treatment were revealed, which may be useful in the clinical setting for monitoring a patient’s therapeutic response