WEE1 inhibition in pancreatic cancer cells is dependent on DNA repair status in a context dependent manner

Shruti Lal, Mahsa Zarei, Saswati N. Chand, Emanuela Dylgjeri, Nicole C. Mambelli-Lisboa, Michael J. Pishvaian, Charles J. Yeo, Jordan M. Winter, Jonathan R. Brody

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number33323
JournalScientific Reports
Volume6
DOIs
StatePublished - Sep 12 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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