Abstract 1781: EGFR amplification-A candidate predictive biomarker of PARP inhibitor Talazoparib sensitivity in gliomas

Abstract

Abstract Poly (ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARP is a promising strategy for targeting cancers with defective DNA-damage repair. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. Glioma Stem Cells (GSCs) exhibit higher oxidative base damage, single-strand DNA breaks and genomic instability and is reliant on single-strand break repair/base excision repair to tolerate additional stress. PARP critical for maintaining genomic stability by regulating a variety of DNA damage repair mechanisms is constitutively activated in GSCs. In this study, we show that talazoparib – a unique PARP inhibitor exhibits a strong single agent activity to inhibit proliferation of GSCs in vitro and suppress tumor progression in GSCs xenografts. Talazoparib cytotoxic activity was through inhibiting PARylation and by trapping PARP-DNA complexes resulting in accumulation of DNA damage during replication and ultimately leading to apoptosis. More importantly, we found EFGR amplification, which occurs in about 45% of GBM as a biomarker of response to PARPi. Gene expression and RPPA data showed that GSCs with EGFR amplification were associated with increased ROS, basal expression of DNA repair proteins and more DNA damage following talazoparib treatment, which may partially explain the sensitivity of this group of GSCs to talazoparib. EGFR enzyme activity was important for PARPi sensitivity since kinase dead mutant of EGFR or EGFR knock down cell lines were resistant to PARPi as was also shown by decreased PARP/DNA complex formation. Talazoparib showed strong inhibition of tumor growth in subcutaneous glioma model and 20% increase in median survival in an intracranial model with a 10% blood brain penetration of talazoparib. These data provide mechanistic insights into the anti-cancer activity of PARP inhibitors with mechanistic rationale of PARP inhibition and potential EGFR amplification as biomarker in the development for precision cancer. Citation Format: Shaofang Wu, Feng Gao, Xiaolong Li, Jie Ding, Siyuan Zheng, Emmanuel Martinez-Ledesma, Ningping Feng, Erik Sulman, Roel Verhaak, John de Groot, Dimpy Koul, W.K.Alfred Yung. EGFR amplification-A candidate predictive biomarker of PARP inhibitor Talazoparib sensitivity in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1781. doi:10.1158/1538-7445.AM2017-1781