DDRE-27. LMNA-PRKDC AXIS PROMOTES CHEMORESISTANCE IN RECURRENT GBM BY STABILIZING DNA REPAIR FOCI

Tumors in patients with recurrent GBM are resistant to standard therapies. Available models for testing experimental therapies to treat GBM are primarily derived from or representative of primary, untreated GBM. We have developed a clinically relevant model of recurrent, therapy-resistant glioblastoma (GBM6R) from a patient-derived xenograft (PDX) of primary glioblastoma (GBM6) that underwent multiple rounds of temozolomide (TMZ) treatment following intracranial engraftment in a host mouse. Initial characterizations of GBM6R revealed a significant decrease in sensitivity to TMZ both in vitro (p< 0.008) and in vivo (p=0.0079). An unbiased screen to identify proteins with altered expression in GBM6R, relative to treatment naïve GBM6, revealed nuclear lamina protein LMNA as highly expressed in GBM6R. From in silico analysis we found that high LMNA expression is associated with poor survival for GBM patients (p=0.0001, Gravendeel; p=0.0078, TCGA_GBM; p< 0.0001, CCGA; GlioVis). GBM5 and GBM43 PDX explant cultures treated with multiple doses of TMZ increased their expression of LMNA. We found that in TMZ treated and TMZ resistant tumors, that LMNA preferentially localizes to the nuclear lamina (p< 0.001), which is not observed in primary, untreated tumors (p< 0.005). Analysis of LMNA by immunoprecipitation revealed that LMNA interacts with DNA-PK and γH2AX. From these results, we hypothesize that LMNA may be acting to stabilize DNA damage foci at the nuclear periphery, which results in enhanced DNA repair. Our observations support the testing of selective DNA-PK inhibitors for treating GBM, which would inhibit TMZ-induced DNA damage repair, and enhance the cytotoxic effects of TMZ.