Ddis-03. Egfr Amplification Induced Increased Dna Damage Response and Predicted Selective Sensitivity to Talazoparib (parp Inhibitor) in Glioblastoma Stem-like Cells
Year: 2018
Type: conference-abstract
Abstract: Poly-ADP-ribose polymerase (PARP) is an enzyme critical for regulating a variety of DNA damage repair mechanisms. In this study, we report that PARP inhibitor, talazoparib, showed strong single-agent cytotoxicity and remarkable selective activity in glioma stem-like cells (GSCs). This single agent activity was strongly correlated with EGFR amplification as shown by genomic analysis. GSCs withEGFR amplification (which occurs in about 45% of GBMs) exhibited higher oxidative base damage, DNA breaks, and genomic instability than non-amplified GSCs. To sustain the elevated basal oxidative stress, EGFR amplified GSCs harbored increased basal expression of DNA repair proteins. As a result, DNA damage and PARP-DNA complexes increased in the amplified GSCs following talazoparib treatment, which may explain the sensitivity of these GSCs to talazoparib. Further, we show that EGFR kinase activity is important for talazoparib sensitivity, as kinase-inactive EGFR mutant and EGFR knockout cell lines were resistant to talazoparib. Intriguingly, another PAPR inhibitor Olaparib, with similar PARP enzymatic inhibition potential but less PARP-trapping ability compared with talazoparib, did not show selective sensitivity in EGFR amplified GSCs. Our data provide insight into the anti-cancer activity of talazoparib through PARP inhibition and by trapping PARP-DNA complexes. In conclusion we propose the potential of EGFR amplification as a biomarker for selection of the development of personalized therapy.
Source: Neuro-Oncology
Authors: Shaofang Wu, Feng Gao, Siyuan Zheng, Chen Zhang, Juan Emmanuel Martinez-Ledesma, Ravesanker Ezhilarasan, Jie Ding, Xiaolong Li, Ningping Feng, Erik Sulman, Roel Verhaak, John de Groot, Tim Heffernan, W K Alfred Yung, Dimpy Koul
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2900234082