Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy.
Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis, EGFR targeted therapies have achieved limited clinical efficacy. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII, an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER) genes required for the repair of Reactive Oxygen Species (ROS)-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1). Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Masayuki
M
Nitta
David
D
Kozono
Richard
R
Kennedy
Jayne
J
Stommel
Kimberly
K
Ng
Pascal O
PO
Zinn
Deepa
D
Kushwaha
Santosh
S
Kesari
Maria-del-Mar
MM
Inda
Jill
J
Wykosky
Frank
F
Furnari
Katherine A
KA
Hoadley
Lynda
L
Chin
Ronald A
RA
DePinho
Webster K
WK
Cavenee
Alan
A
D'Andrea
Clark C
CC
Chen
D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D006801:Humans; D018384:Oxidative Stress; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011836:Radiation Tolerance; D017382:Reactive Oxygen Species / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D066246:ErbB Receptors