Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

Significance Glioblastoma is the most common and aggressive type of glioma, with a median survival of 15 mo. A major obstacle to effective treatment is de novo or acquired resistance to standard-care therapies, including radiation and temozolomide. Enhanced DNA repair can allow damaged or mutated cells to survive, contributing to resistance and tumor recurrence. We have identified Akt3 as the dominant Akt isoform that robustly stimulates glioma progression. We also discovered key roles for Akt3 in activating DNA repair pathways, which led to enhanced survival of human glioblastoma cells following radiation or temozolomide treatment. Our work has potential broad application to multiple cancer types in which Akt3 is expressed. Blocking this pathway may help prevent or alleviate DNA repair-mediated therapeutic resistance.