Abstract B16: Cells containing mutations in the cohesin component, STAG2, are sensitive to PARP inhibition

Abstract

Abstract Synthetic lethality (SL) has been proposed as a strategy to specifically target cells harboring cancer mutations while leaving unmutated, non-cancer cells unaffected, thus minimizing drug side effects. One genetic vulnerability common to many types of cancer is chromosome instability (or CIN). CIN can lead to increased genetic mutation and aneuploidy in cancer cells thereby distinguishing them from their normal neighbors and making it a possible candidate phenotype to target by SL. Here, we focus on the multifunctional cohesin complex that is critical for accurate chromosome segregation and genome stability because it tethers sister chromatids together after DNA replication and maintains cohesion until their separation in anaphase. Although several subunits of cohesin have been shown to be mutated in tumors, recent data identifies a cohesin component, STAG2 (Stromal Antigen 2 or SA-2) as a highly mutated gene in several types of cancer including Ewing's sarcoma, melanoma and glioblastomas (GBMs). As a previous study in our lab had shown that knockdown of any one of the core cohesion subunits SMC1A, SMC3 or RAD21 can render cells sensitive to the poly ADP-ribose polymerase (PARP) inhibitor olaparib, we sought to determine if cell lines harboring cancer-specific STAG2 mutations showed similar sensitivity. Using paired GBM cell lines containing either a truncated STAG2 or wild-type STAG2 knock-in, we found that STAG2 mutation status was, indeed, associated with significantly decreased proliferation in the presence of PARP inhibition. Interestingly, olaparib treatment led to an accumulation of cells in the G2 phase of the cell cycle and an increase in DNA damage markers. Furthermore, in the presence of increasing concentrations of olaparib, a higher percentage of STAG2-mutated cells had micronuclei and fragmented nuclei compared to their wild-type STAG2 knock-in counterparts. Taken together, these data suggest that the DNA repair enzyme PARP may be a potential therapeutic SL target for tumors harboring mutations in STAG2. Citation Format: Melanie L. Bailey, Nigel J. O'Neil, Derek M. van Pel, Phil Hieter. Cells containing mutations in the cohesin component, STAG2, are sensitive to PARP inhibition. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B16.