PURPOSE: Over 90% of PC express oncogenic mutant @entity984 that constitutively activates the Raf- @entity8047 -MAPK pathway conferring resistance to both radiation and chemotherapy. @entity8047 inhibitors have shown promising anti- @entity5 responses in recent preclinical and clinical studies, and are currently being tested in combination with radiation in clinical trials. Here, we have evaluated the radiosensitizing potential of a novel @entity16629 inhibitor @entity5459 ( @entity68960 ) and evaluated whether @entity16629 inhibition alters DNA repair mechanisms in multiple PC cell lines. METHODS: Radiosensitization and DNA double-strand break (DSB) repair were evaluated by clonogenic assays, comet assay, nuclear foci formation (yH2AX, @entity10322 , 53BP1, @entity5345 , and @entity6545 ), and by functional GFP-reporter assays for homologous recombination (HR) and non-homologous end-joining (NHEJ). Expression and activation of DNA repair proteins were measured by immunoblotting. RESULTS: @entity68960 blocked @entity1366 activity and radiosensitized multiple @entity984 mutant PC cell lines. Prolonged pre-treatment with @entity68960 for 24-48  hours was required to observe significant radiosensitization. @entity68960 treatment resulted in delayed resolution of DNA damage by comet assays and persistent yH2AX nuclear foci. @entity68960 treatment also resulted in altered @entity5345 , @entity6545 , @entity10322 , and 53BP1 nuclear foci appearance and resolution after radiation. Using functional reporters, @entity68960 caused repression of both HR and NHEJ repair activity. Moreover, @entity68960 suppressed the expression and activation of a number of DSB repair pathway intermediates including @entity5345 , @entity10322 , @entity6545 , @entity16071 , and @entity23902 . CONCLUSION: @entity68960 confers radiosensitization to @entity984 -driven PC cells by suppressing major DNA-DSB repair pathways. These data provide support for the combination of @entity16629 inhibition and radiation in the treatment of PC.

XXXX Inhibitor @entity5459 -Mediated Radiosensitization of Pancreatic Cancer Cells Involves Inhibition of DNA Double-Strand Break Repair Pathways.

@entity68960 :: ('MESH:C561454', 'Chemical') :: ['GSK212'] @entity8047 :: ('5609', 'Gene') :: ['MEK'] @entity5459 :: ('MESH:C560077', 'Chemical') :: ['GSK1120212'] @entity984 :: ('3845', 'Gene') :: ['KRAS'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor'] @entity5345 :: ('672', 'Gene') :: ['BRCA1'] @entity16629 :: ('5604;5605', 'Gene') :: ['MEK1/2'] @entity6545 :: ('5888', 'Gene') :: ['RAD51'] @entity23902 :: ('1111', 'Gene') :: ['Chk-1'] @entity10322 :: ('5591', 'Gene') :: ['DNA-PK'] @entity1366 :: ('5595;5594', 'Gene') :: ['ERK1/2'] @entity16071 :: ('6241', 'Gene') :: ['RRM2']
@entity8047 :: (5609,Gene) :: ['MEK']
