Genetically defined subsets of human pancreatic cancer show unique in vitro chemosensitivity

Clin Cancer Res. 2012 Dec 1;18(23):6519-30. doi: 10.1158/1078-0432.CCR-12-0827. Epub 2012 Jul 2.


Purpose: Pancreatic cancer is the fourth cause of death from cancer in the western world. Majority of patients present with advanced unresectable disease responding poorly to most chemotherapeutic agents. Chemotherapy for pancreatic cancer might be improved by adjusting it to individual genetic profiles. We attempt to identify genetic predictors of chemosensitivity to broad classes of anticancer drugs.

Experimental design: Using a panel of genetically defined human pancreatic cancer cell lines, we tested gemcitabine (antimetabolite), docetaxel (antimicrotubule), mitomycin C (MMC; alkylating), irinotecan (topoisomerase I inhibitor), cisplatin (crosslinking), KU0058948 (Parp1 inhibitor), triptolide (terpenoid drug), and artemisinin (control).

Results: All pancreatic cancer cell lines were sensitive to triptolide and docetaxel. Most pancreatic cancer cells were also sensitive to gemcitabine and MMC. The vast majority of pancreatic cancer cell lines were insensitive to cisplatin, irinotecan, and a Parp1 inhibitor. However, individual cell lines were often sensitive to these compounds in unique ways. We found that DPC4/SMAD4 inactivation sensitized pancreatic cancer cells to cisplatin and irinotecan by 2- to 4-fold, but they were modestly less sensitive to gemcitabine. Pancreatic cancer cells were all sensitive to triptolide and 18% were sensitive to the Parp1 inhibitor. P16/CDKN2A-inactivated pancreatic cancer cells were 3- to 4-fold less sensitive to gemcitabine and MMC.

Conclusions: Chemosensitivity of pancreatic cancer cells correlated with some specific genetic profiles. These results support the hypothesis that genetic subsets of pancreatic cancer exist, and these genetic backgrounds may permit one to personalize the chemotherapy of pancreatic cancer in the future. Further work will need to confirm these responses and determine their magnitude in vivo.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cluster Analysis
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Drug Screening Assays, Antitumor
  • Humans
  • Inhibitory Concentration 50
  • Mutation
  • Pancreatic Neoplasms / classification
  • Pancreatic Neoplasms / genetics*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Smad4 Protein / genetics
  • Tumor Suppressor Protein p53 / genetics


  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p16
  • Poly(ADP-ribose) Polymerase Inhibitors
  • SMAD4 protein, human
  • Smad4 Protein
  • Tumor Suppressor Protein p53
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1