Parp targeting counteracts gliomagenesis through promotion of genomic instability in pten-mutant glioma and downregulation of survival pathways
Majuelos-Melguizo J1, Rodríguez MI1, López-Jiménez L1, Rodríguez-Vargas JM1, Martí Martín-Consuegra J1, Serrano-Sáenz S1, Gavard J3, Ruiz de Almodóvar JM2 and Oliver FJ1.
1 Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain
2 IBIMER, Centro de Investigación Biomédica, Universidad de Granada, Spain
3 CNRS, UMR8104, Paris, France
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. 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 mutant cells, PARPi induced genomic instability, exacerbated homologous recombination (HR) repair deficiency, and down-regulated the Spindle Assembly Checkpoint (SAC) factor BUBR1.
EGFR amplification is another frequent alteration in GBM. In addition, PARPi prevented EGFR-mTOR axis activation, inducing autophagy and impacting on lipid droplets formation. 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 targets PTEN-deficient GBM cells through the induction of genomic instability and eventually deriving to mitotic catastrophe; 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.