Gemcitabine based treatment is currently a standard first line treatment for patients with advanced
pancreatic cancer, however overall survival remains poor, and few options are available for patients that fail
gemcitabine based
therapy. To identify potential molecular targets in
gemcitabine refractory
pancreatic cancer, we developed a series of
gemcitabine resistant (GR) cell lines. Initial drug exposure selected for an early resistant phenotype that was independent of drug metabolic pathways. Prolonged drug selection pressure after 16 weeks, led to an induction of
cytidine deaminase (CDA) and enhanced drug detoxification. Cross resistance profiles demonstrate approximately 100-fold cross resistance to the
pyrimidine nucleoside cytarabine, but no resistance to the same in class agents,
azacytidine and
decitabine. GR cell lines demonstrated a dose dependent collateral
hypersensitivity to class I and II
histone deacetylase (
HDAC) inhibitors and decreased expression of 3 different global
heterochromatin marks, as detected by H4K20me3, H3K9me3 and H3K27me3. Cell morphology of the drug resistant cell lines demonstrated a fibroblastic type appearance with loss of cell-cell junctions and an altered microarray expression pattern, using Gene Ontology (GO) annotation, consistent with progression to an invasive phenotype. Of particular note, the
gemcitabine resistant cell lines displayed up to a 15 fold increase in invasive potential that directly correlates with the level of
gemcitabine resistance. These findings suggest a mechanistic relationship between chemoresistance and metastatic potential in
pancreatic carcinoma and provide evidence for molecular pathways that may be exploited to develop therapeutic strategies for refractory
pancreatic cancer.