UNASSIGNED: @entity463 is the most common form of primary @entity1313 in adults and is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, @entity5 recurrence is inevitable and is thought to be driven by @entity463 stem-like cells (GSC) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary @entity1 -derived @entity463 cell lines, we confirmed by clonogenic survival assays that GSCs were significantly more radioresistant than paired @entity5 bulk populations. DNA damage response targets ATM, @entity15126 , @entity23902 , and @entity12982 were upregulated in GSCs, and @entity23902 was preferentially activated following irradiation. Consequently, GSCs exhibit rapid G2-M cell-cycle checkpoint activation and enhanced DNA repair. Inhibition of @entity23902 or @entity15126 successfully abrogated G2-M checkpoint function, leading to increased mitotic catastrophe and a modest increase in radiation sensitivity. Inhibition of ATM had dual effects on cell-cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects on GSCs than inhibition of @entity23902 , @entity15126 , or @entity12982 alone. Combined inhibition of @entity12982 and @entity15126 resulted in a profound radiosensitization of GSCs, which was of greater magnitude than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radioresistance of GSC. @entity5 Res; 75(20); 1-13.   2015 AACR.

Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of XXXX Stem-like Cells.

@entity1 :: ('9606', 'Species') :: ['patient'] @entity15126 :: ('545', 'Gene') :: ['ATR'] @entity1313 :: ('MESH:D001932', 'Disease') :: ['brain tumor'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'Cancer'] @entity12982 :: ('142', 'Gene') :: ['PARP', 'PARP1'] @entity23902 :: ('1111', 'Gene') :: ['CHK1'] @entity463 :: ('MESH:D005909', 'Disease') :: ['glioblastoma', 'Glioblastoma']
@entity463 :: (MESH:D005909,Disease) :: ['Glioblastoma']
