ATPS-54GENOMICALLY UNSTABLE GLIOBLASTOMA (U-GBM) SHOW EXQUISITE SENSITIVITY TO PARP INHIBITION

BACKGROUND: The development of effective targeted drugs for the treatment of glioblastoma (GBM) represents a major unmet need. Veliparib (ABT-888; Abbvie) inhibits both PARP1 and PARP2 (poly[ADP-ribose] polymerase). The successful clinical application of veliparib and other PARP inhibitors (PARPi) will be assisted by the identification of predictive biomarkers. METHODS: We performed whole genome sequencing (WGS) on ten GBM specimens with matched normal DNA. Mutations were detected using qSNP and GATK and indels called with Pindel and GATK. Somatic structural variants were identified using the qSV package. We tested the efficacy of the combination of veliparib and radiotherapy (RT) in vitro using patient derived cell lines (PDCLs) and in vivo using our patient derived xenograft (PDX) model. RESULTS: Strikingly, in 2 patient samples denoted as G89 and G54, the mutation rate was at least 16-fold higher compared to the other 8 participants. G89 and G54 exhibited a large number of single nucleotide variants (SNVs), insertions, deletions and structural variant (SV) events (>2 million) when compared to the other 8 patient samples. The scale of genomic instability suggested defects in DNA maintenance, which could potentially define sensitivity to DNA damaging agents. Upon closer examination of the mutational profile of G89 and G54, mutations were found in at least one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. We also detected mutations in other genes involved in DNA maintenance such as XRCC4, FANCA, FANCD2, ATR, RPA1, and REV3L. We designated these patients' GBM as U-GBM class. We found the U-GBM class of tumors, G89 and G54 to be hypersensitive to the combination of veliparib and RT, both in vitro and in vivo. CONCLUSION: Mutations in DNA maintenance pathways may be a method for selecting patients for therapies involving the combination of DNA damaging agents such as radiotherapy, and PARP inhibitors.