PDF file, 127K, S8 IC50s of DPC4/SMAD4 isogenic cells tested with Cisplatin, Irinotecan and Gemcitabine; S9 Correlation analysis between IC50s of Cisplatin, Irinotecan and Gemcitabine and TGFB pathway activity of DPC4 isogenic cells; S10 Genes whose expression levels were correlated with chemosensitivity in pancreatic cancer cell lines; S11 Combination indices (CI) for csplatin+irinotecan combination in DPC4 isogenic cell lines; S12 IC50s of TP53 isogenic colon cancer cell lines tested with Parp1 inhibitor and Triptolide; S13 Comparisons of gene mutation statuses of cell lines having IC50<200nM with those having IC50>10000nM for Parp1 inhibitor; S14 Genes with significantly different gene expression in cell cycle and DNA damage pathway and other DNA damage repair genes without significant difference between TP53 defective PC cell lines having IC50<200nM and those having IC50>10000nM for Parp1 inhibitor; S15 P16/CDKN2A deleted PC cells rank ordered by their sensitivity to gemcitabine and MMC investigated for association with CDKN2B, DMRTA1, MTAP and TUSC1 in pancreatic cancer cells.
ARTICLE ABSTRACT
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. Clin Cancer Res; 18(23); 6519–30. ©2012 AACR.
