WEE1 inhibition in pancreatic cancer cells is dependent on DNA repair status in a context dependent manner.
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease, in part, because of the lack of effective targeted therapeutic options. MK-1775 (also known as AZD1775), a mitotic inhibitor, has been demonstrated to enhance the anti-tumor effects of DNA damaging agents such as gemcitabine. We evaluated the efficacy of MK-1775 alone or in combination with DNA damaging agents (MMC or oxaliplatin) in PDA cell lines that are either DNA repair proficient (DDR-P) or deficient (DDR-D). PDA cell lines PL11, Hs 766T and Capan-1 harboring naturally selected mutations in DNA repair genes FANCC, FANCG and BRCA2 respectively, were less sensitive to MK-1775 as compared to two out of four representative DDR-P (MIA PaCa2 and PANC-1) cell lines. Accordingly, DDR-P cells exhibit reduced sensitivity to MK-1775 upon siRNA silencing of DNA repair genes, BRCA2 or FANCD2, compared to control cells. Only DDR-P cells showed increased apoptosis as a result of early mitotic entry and catastrophe compared to DDR-D cells. Taken together with other recently published reports, our results add another level of evidence that the efficacy of WEE1 inhibition is influenced by the DNA repair status of a cell and may also be dependent on the tumor type and model evaluated.
Department of Surgery, Division of Surgical Research; Jefferson Pancreas, Biliary and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University, Philadelphia, PA, USA.
Shruti
S
Lal
Department of Surgery, Division of Surgical Research; Jefferson Pancreas, Biliary and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University, Philadelphia, PA, USA.
Mahsa
M
Zarei
Department of Surgery, Division of Surgical Research; Jefferson Pancreas, Biliary and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University, Philadelphia, PA, USA.
Saswati N
SN
Chand
Department of Surgery, Division of Surgical Research; Jefferson Pancreas, Biliary and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University, Philadelphia, PA, USA.
Emanuela
E
Dylgjeri
Department of Surgery, Division of Surgical Research; Jefferson Pancreas, Biliary and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University, Philadelphia, PA, USA.
Nicole C
NC
Mambelli-Lisboa
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Road, NW, 20057 Washington DC, USA.
Michael J
MJ
Pishvaian
Department of Surgery, Division of Surgical Research; Jefferson Pancreas, Biliary and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University, Philadelphia, PA, USA.
Charles J
CJ
Yeo
Department of Surgery, Division of Surgical Research; Jefferson Pancreas, Biliary and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University, Philadelphia, PA, USA.
Jordan M
JM
Winter
Department of Surgery, Division of Surgical Research; Jefferson Pancreas, Biliary and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University, Philadelphia, PA, USA.
Jonathan R
JR
Brody
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D045643:DNA Repair Enzymes / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D016685:Mitomycin / Q000494:pharmacology; D008938:Mitosis; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009153:Mutagens; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D000077150:Oxaliplatin; D016685:Mitomycin; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D045643:DNA Repair Enzymes; C549567:adavosertib