PARP TARGETING COUNTERACTS GLIOMAGENESIS THROUGH PROMOTION OF CHROMOSOMAL INSTABILITY AND AGGRAVATION OF DEFICIENCY IN HOMOLOGOUS RECOMBINATION REPAIR IN PTEN-MUTANT GLIOMA

Majuelos-Melguizo J, Rodríguez MI, López-Jiménez L, Rodríguez-Vargas JM, Martí Martín-Consuegra J, Serrano-Sáenz S, Gavard J, Ruiz de Almodóvar JM and Oliver FJ.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, with a poor median survival of 14 months.
In our laboratory, we are interested in the role of poly(ADP-ribose)polymerase (PARP) in tumor development. Specifically, PARP-1 is a nuclear protein involved in multiple facets of DNA repair and transcriptional regulation. In this study, we dissected the action of PARP inhibition (PARPi) in GBM cell lines with either functional or mutated PTEN that confers resistance to diverse therapies. In PTEN deficient cells, PARPi exacerbated homologous recombination repair deficiency and down-regulated the Spindle Assembly Checkpoint factor BUBR1, leading to the induction of genomic and chromosomal instability and eventually deriving to mitotic catastrophe.

EGFR amplification is another frequent alteration in GBM. To more effectively target GBM cells, co-treatment with PARPi and an EGFR blocker, erlotinib, resulted in a strong suppression of ERK1/2 activation and in vivo the combined effect elicited a robust reduction in tumor development. In conclusion, PARPi results in a profound alteration of genomic and chromosomal stability that compromises cell viability in PTEN-deficient GBM; besides, PARPi inhibits survival pathways and the co-treatment with erlotinib strongly retarded in vivo gliomagenesis.
Thus, taking advantage of PARPi-induced cell death in PTEN-mutant glioma cells prone to genomic instability, and disabling survival pathways through the combined inhibition of EGFR and PARP could be therapeutically exploited in the treatment of this malignant tumor.

PARP targeting counteracts gliomagenesis through induction of mitotic catastrophe and aggravation of deficiency in homologous recombination in PTEN-mutant glioma.

Oncotarget. 2015 Mar 10;6(7):4790-803.