CSIG-40. PHOSPHOGLYCERATE MUTASE 1 (PGAM1) ACTIVATES DNA DAMAGE REPAIR VIA REGULATION OF WIP1 ACTIVITY

In normal cells, phosphoglycerate mutase 1(PGAM1) converts 3-phospho glycerate to 2-phospho glycerate. PGAM1, however is overexpressed in different forms of cancer and has been suggested to have additional functions beyond its role in metabolism. We here report that PGAM1 is overexpressed in GBMs and by indirectly increasing the efficiency of DNA damage repair, increases resistance to radiation (IR) and temozolomide (TMZ) treatment. Specifically, suppression of PGAM1 in multiple GBM cell lines decreased gH2AX foci, increased apoptosis and decreased clonagenicity relative to control cells following exposure to radiation and TMZ. In control GBM cells PGAM1 co-immunoprecipitated with WIP1, a phosphatase reported to bind and dephosphorylate ATM, Chk1, and Chk2. Binding of PGAM1 biochemically inactivated the phosphatase activity of WIP1 leaving ATM and its downstream substrates phosphorylated and active in DNA repair. In contrast, in isogenic PGAM1 knockdown cells, WIP1 bound and dephosphorylated ATM at s1981, further limiting the downstream phosphorylation of Chk1, Chk2 and cdc25C (s216). Furthermore, genetic or pharmacological ablation of WIP1 in PGAM1 knockdown cells rescued ATM, Chk1 and Chk2 phosphorylation, downstream signaling, and IR/TMZ sensitivity. Consistent with these observations, mice intracranially implanted with PGAM1 knockdown GBM cells and treated with TMZ and IR had longer survival than similarly treated mice implanted with matched control cells. These results therefore define the metabolic enzyme PGAM1 as an activator of DNA damage repair pathway and a therapeutically targetable regulator of drug response in GBM.